MODELLING COMPLEX BIOLOGICAL SYSTEMS IN THE CONTEXT OF GENOMICS                       Evry, May 21-25, 2012On the cellular...
Quantitative Organism Biology Cells of multicellular organism cooperate to ensure bodydevelopment and maintenance. They do...
http://www.embl-heidelberg.de/digitalembryo/
How cells get along without a GPS ?
How cells get along without a GPS ?            global information (system)
autoimmune disease and immunopathology,                                                   2                      2        ...
autoimmune disease and immunopathology,                                                   2                      2        ...
autoimmune disease and immunopathology,                                                   2                      2        ...
overviewTolerance, autoimmunity, and regulatory T cellsRegulatory T cells 101How regulatory T cells mediate tolerance ?Mod...
What does the immune system do in the vertebrate organism?
Fighting infection
Fighting infectionAssimilatingintestinal flora
Fighting infectionAssimilatingintestinal flora    Rejecting cancer cells
Fighting infectionAssimilatingintestinal flora                             House keeping    Rejecting cancer cells
Homeostasis   Fighting infection          and RegulationAssimilatingintestinal flora                             House kee...
Homeostasis   Fighting infection                                                                                  and Regu...
Failure of homeostasis and regulation unleashes pathologic autoimmunity
Failure of homeostasis and regulation unleashes pathologic autoimmunity    Rheumatoid arthritis                           ...
From: Jean-François Bach, New England J Med
“In general, the management of human systemicautoimmune disease is empirical and unsatisfactory. For themost part, broadly...
Clonal selection theory                                                      Stem CellJerne, 1953Burnet, 1957             ...
CTL                                        CTL                             CTL                    CTL                 CTL ...
CTL                                        CTL                             CTL                    CTL                 CTL ...
CTL                                        CTL                             CTL                    CTL                 CTL ...
CTL                                        CTL                             CTL                    CTL                 CTL ...
CTL                                        CTL                             CTL                    CTL                 CTL ...
Reductionist molecular biology approach to Immunology
TOLERANCE = absence of clonal expansion = CLONAL DELETION         Therapy of autoimmune diseases should aim at            ...
Is there any hope ?
Tolerance is mediated by regulatory T cellsMason-Sakaguchi   WT
Tolerance is mediated by regulatory T cellsMason-Sakaguchi              CD25- CD4+ T cells                        E E E   ...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                              “empty” rag-/-    ...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                              “empty” rag-/-    ...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cellsMason-Sakaguchi                                                  “empty” rag-/-...
Tolerance is mediated by regulatory T cells                                         CTL                                   ...
TOLERANCE = absence of clonal expansion = control by regulatory T cells         Therapy of autoimmune diseases should aim ...
… BUT …there are many open questions
CD25+CD4+T cells                      R              R      R   R               R      R           R              R (Regul...
What makes a T cellbe a regulatory T cell ?                    CD25+CD4+T cells                                           ...
What makes a T cell    be a regulatory T cell ?                        CD25+CD4+T cells                                   ...
What makes a T cell    be a regulatory T cell ?                        CD25+CD4+T cells                                   ...
What makes a T cell    be a regulatory T cell ?                        CD25+CD4+T cells                                   ...
What makes a T cell    be a regulatory T cell ?                                                             How many and h...
How does their repertoire     What makes a T cell                       compare to that of other T    be a regulatory T ce...
Balance between regulatory and effector T cell subpopulations
Is it that simple ?
Is it that simple ?“Everything should be made as simple as possible,                                But not simpler.”     ...
http://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
http://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
http://www.sewingmachines.us/sewing-machine-636.jpghttp://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
http://www.sewingmachines.us/sewing-machine-636.jpg                                                                      h...
http://web.mit.edu/2.972/www/reports/sewing_machine/a-sewing_machine.gif
Cell population dynamics
J. theor. Biol. (2000) 207, 231}254                         doi:10.1006/jtbi.2000.2169, available online at http://www.ide...
Modelling T cell population dynamicsnet growth = influx       + interaction-dependent   — death                            ...
Modelling T cell population dynamicsnet growth = influx       + interaction-dependent   — death                            ...
Modelling T cell population dynamicsnet growth = influx       + interaction-dependent   — death                            ...
Modelling T cell population dynamicsnet growth = influx       + interaction-dependent   — death                            ...
Modelling T cell population dynamicsnet growth = influx       + interaction-dependent   — death                            ...
Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction                         ...
Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction                         ...
Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction                         ...
Modelling T cell population dynamics: the crossregulation model                      Interactive simulation
Quantitative assay for cell proliferation+CFSE                Nº Cells                                            Log FL1-...
Putting the CRM to the test                                                                                      + anti-CD...
Putting the CRM to the test                                                                                    + anti-CD3 ...
Putting the CRM to the test                                                                                    + anti-CD3 ...
Putting the CRM to the test                                                                                    + anti-CD3 ...
Putting the CRM to the test                                                                                    + anti-CD3 ...
Putting the CRM to the test                                                                                    + anti-CD3 ...
Putting the CRM to the test                                                                                               ...
Putting the CRM to the test Proportions              Effector Cells                Regulatory CellsThy1.1:Thy1.2          ...
Modelling T cell population dynamics: the crossregulation model                                                           ...
Modelling T cell population dynamics: the crossregulation model         Regulatory T cell populations grow as a           ...
the control of the insulin promoter. We had previously observedModelling T cell population dynamics: the crossregulation m...
How does their repertoire     What makes a T cell                       compare to that of other T    be a regulatory T ce...
How does their repertoire     What makes a T cell                       compare to that of other T    be a regulatory T ce...
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    1. 1. MODELLING COMPLEX BIOLOGICAL SYSTEMS IN THE CONTEXT OF GENOMICS Evry, May 21-25, 2012On the cellular and supracellular networks controlling regulatory T cells and autoimmunity Jorge Carneiro Instituto Gulbenkian de Ciência, Portugal http://qobweb.igc.gulbenkian.pt
    2. 2. Quantitative Organism Biology Cells of multicellular organism cooperate to ensure bodydevelopment and maintenance. They do this in a collective distributed manner, without a global plan. How cells collectively generate organism’s properties? General principles of biological organisation The design and control of artificial systems
    3. 3. http://www.embl-heidelberg.de/digitalembryo/
    4. 4. How cells get along without a GPS ?
    5. 5. How cells get along without a GPS ? global information (system)
    6. 6. autoimmune disease and immunopathology, 2 2 2 2 B Foxp3 represents a more specific marker than 5RBhi alone +Foxp3/MIGR1 +MIGR1 None CD25-CD45RBhi alone cell-surface molecules (such as currently used +Foxp3/MIGR1 +MIGR1 None CD25, CD45RB, CTLA-4, and GITR), which Multiple are unable to completely discriminate between regulatory T cells and activated, effector, or memory T cells. scales Colon Mutations in the Foxp3 gene culminate in the development of a fatal lymphoprolifera- tive disorder associated with multiorgan pa- thology both in mice and humans (12–20). FOXP3 is predominantly expressed in human CD25ϩCD4ϩ T cells as well (32). Further- Stomach more, transduction of a mutant Foxp3 lacking the forkhead domain, similar to the mutated Foxp3 in scurfy mice (17), failed to confer suppressive activity to CD25–CD4ϩ T cells Fig. 4. Prevention(fig.IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid of S7). The present results therefore sug- 105 fresh CD25–CD45RBhighCD4ϩ cells either alone (n ϭ 6, where n is the 4 ϫ 10that mutations of thehighCD4ϩgene may alone (n ϭ 6, where n is the mice received gest 5 fresh CD25–CD45RB Foxp3 cells either derived of mice)cause squares)disorders through1.2develop- GFPϩ sorted cells derived from pen squares) or together with 1.2 ϫ 106 GFPϩ sorted cells number from (open these or together with ϫ 106D4ϩ cells infected with Foxp3/MIGR1 (n ϭ 7) (closed circles) or MIGR1 –(n ϭ 5) highmentalcells infected with Foxp3/MIGR1 (n ϭthe (closed circles) or MIGR1 (n ϭ 5) CD25 CD45RB CD4ϩ or functional abnormality of 7) weight is represented as the percentage of initial weight (mean Ϯ SD). Body weight is represented as the percentage of initial weight (mean Ϯ SD) (open circles). CD25ϩCD4ϩ T population. R gnificant difference, P Ͻ 0.01, Foxp3/MIGR1 versus other two groups indicate significant difference, P of T cells by Foxp3 versus other two groups by Astericks by Potentially, generation Ͻ 0.01, Foxp3/MIGR1 R (B) Histopathology of the colon and stomach in each group and in an test. (B) Histopathology of the colon and stomach in each group and in an Mann-Whitney transduction of naıve T cells may provide a ¨ D mouse (None). (C) Colitis (left) and gastritis (right) were unreconstituted SCID mouse (None). (C) Colitis (left) and gastritis (right) were histologically histologically the group cotransferred with MIGR1-infected cells and one transferredTwo micepreviously unstudied therapeutic mode for cells and one transferred with scored. with in the group cotransferred with MIGR1-infected ϩ CD25 CD45RB treatment of autoimmunedebilitation before histological examination. Results –D4 cells alone died of debilitation before histological examination. Results high CD4ϩ cells alone died of and inflammatory are from a total of three independent experiments. shown in (A) to (C) are from a total of three independent experiments. diseases and in transplantation tolerance. 1060 14 FEBRUARY 2003 VOL 299 SCIENCE www.sciencemag.org 14 FEBRUARY 2003 VOL 299 SCIENCE www.scien
    7. 7. autoimmune disease and immunopathology, 2 2 2 2 B Foxp3 represents a more specific marker than 5RBhi alone +Foxp3/MIGR1 +MIGR1 None CD25-CD45RBhi alone cell-surface molecules (such as currently used +Foxp3/MIGR1 +MIGR1 None CD25, CD45RB, CTLA-4, and GITR), which Multiple are unable to completely discriminate between regulatory T cells and activated, effector, or memory T cells. scales Colon Mutations in the Foxp3 gene culminate in the development of a fatal lymphoprolifera- tive disorder associated with multiorgan pa- thology both in mice and humans (12–20). FOXP3 is predominantly expressed in human CD25ϩCD4ϩ T cells as well (32). Further- Stomach more, transduction of a mutant Foxp3 lacking the forkhead domain, similar to the mutated Foxp3 in scurfy mice (17), failed to confer suppressive activity to CD25–CD4ϩ T cells Fig. 4. Prevention(fig.IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid of S7). The present results therefore sug- 105 fresh CD25–CD45RBhighCD4ϩ cells either alone (n ϭ 6, where n is the 4 ϫ 10that mutations of thehighCD4ϩgene may alone (n ϭ 6, where n is the mice received gest 5 fresh CD25–CD45RB Foxp3 cells either derived of mice)cause squares)disorders through1.2develop- GFPϩ sorted cells derived from pen squares) or together with 1.2 ϫ 106 GFPϩ sorted cells number from (open these or together with ϫ 106D4ϩ cells infected with Foxp3/MIGR1 (n ϭ 7) (closed circles) or MIGR1 –(n ϭ 5) highmentalcells infected with Foxp3/MIGR1 (n ϭthe (closed circles) or MIGR1 (n ϭ 5) CD25 CD45RB CD4ϩ or functional abnormality of 7) Astericks by R Cell population dynamics weight is represented as the percentage of initial weight (mean Ϯ SD). Body weight is represented as the percentage of initial weight (mean Ϯ SD) (open circles). CD25ϩCD4ϩ T population. gnificant difference, P Ͻ 0.01, Foxp3/MIGR1 versus other two groups indicate significant difference, P of T cells by Foxp3 versus other two groups by Potentially, generation Ͻ 0.01, Foxp3/MIGR1 (ODE) R (B) Histopathology of the colon and stomach in each group and in an test. (B) Histopathology of the colon and stomach in each group and in an Mann-Whitney transduction of naıve T cells may provide a ¨ D mouse (None). (C) Colitis (left) and gastritis (right) were unreconstituted SCID mouse (None). (C) Colitis (left) and gastritis (right) were histologically histologically the group cotransferred with MIGR1-infected cells and one transferredTwo micepreviously unstudied therapeutic mode for cells and one transferred with scored. with in the group cotransferred with MIGR1-infected ϩ CD25 CD45RB treatment of autoimmunedebilitation before histological examination. Results –D4 cells alone died of debilitation before histological examination. Results high CD4ϩ cells alone died of and inflammatory are from a total of three independent experiments. shown in (A) to (C) are from a total of three independent experiments. diseases and in transplantation tolerance. 1060 14 FEBRUARY 2003 VOL 299 SCIENCE www.sciencemag.org 14 FEBRUARY 2003 VOL 299 SCIENCE www.scien
    8. 8. autoimmune disease and immunopathology, 2 2 2 2 B Foxp3 represents a more specific marker than 5RBhi alone +Foxp3/MIGR1 +MIGR1 None CD25-CD45RBhi alone cell-surface molecules (such as currently used +Foxp3/MIGR1 +MIGR1 None CD25, CD45RB, CTLA-4, and GITR), which Multiple are unable to completely discriminate between regulatory T cells and activated, effector, or memory T cells. scales Colon Mutations in the Foxp3 gene culminate in the development of a fatal lymphoprolifera- tive disorder associated with multiorgan pa- thology both in mice and humans (12–20). FOXP3 is predominantly expressed in human CD25ϩCD4ϩ T cells as well (32). Further- Stomach more, transduction of a mutant Foxp3 lacking the forkhead domain, similar to the mutated Foxp3 in scurfy mice (17), failed to confer suppressive activity to CD25–CD4ϩ T cells Fig. 4. Prevention(fig.IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid IBD and autoimmune gastritis by Foxp3-transduced T cells. (A) C.B-17 scid of S7). The present results therefore sug- 105 fresh CD25–CD45RBhighCD4ϩ cells either alone (n ϭ 6, where n is the 4 ϫ 10that mutations of thehighCD4ϩgene may alone (n ϭ 6, where n is the mice received gest 5 fresh CD25–CD45RB Foxp3 cells either derived of mice)cause squares)disorders through1.2develop- GFPϩ sorted cells derived from pen squares) or together with 1.2 ϫ 106 GFPϩ sorted cells number from (open these or together with ϫ 106D4ϩ cells infected with Foxp3/MIGR1 (n ϭ 7) (closed circles) or MIGR1 –(n ϭ 5) highmentalcells infected with Foxp3/MIGR1 (n ϭthe (closed circles) or MIGR1 (n ϭ 5) CD25 CD45RB CD4ϩ or functional abnormality of 7) Astericks by R Cell population dynamics weight is represented as the percentage of initial weight (mean Ϯ SD). Body weight is represented as the percentage of initial weight (mean Ϯ SD) (open circles). CD25ϩCD4ϩ T population. gnificant difference, P Ͻ 0.01, Foxp3/MIGR1 versus other two groups indicate significant difference, P of T cells by Foxp3 versus other two groups by Potentially, generation Ͻ 0.01, Foxp3/MIGR1 (ODE) R (B) Histopathology of the colon and stomach in each group and in an test. (B) Histopathology of the colon and stomach in each group and in an Mann-Whitney transduction of naıve T cells may provide a ¨ D mouse (None). (C) Colitis (left) and gastritis (right) were unreconstituted SCID mouse (None). (C) Colitis (left) and gastritis (right) were histologically histologically the group cotransferred with MIGR1-infected cells and one transferredTwo micepreviously unstudied therapeutic mode for cells and one transferred with scored. with in the group cotransferred with MIGR1-infected ϩ CD25 CD45RB treatment of autoimmunedebilitation before histological examination. Results –D4 cells alone died of debilitation before histological examination. Results high CD4ϩ cells alone died of and inflammatory are from a total of three independent experiments. shown in (A) to (C) are from a total of three independent experiments. diseases and in transplantation tolerance. 1060 14 FEBRUARY 2003 VOL 299 SCIENCE www.sciencemag.org 14 FEBRUARY 2003 VOL 299 SCIENCE www.scien Gene regulatory networks (Logical network dynamics)
    9. 9. overviewTolerance, autoimmunity, and regulatory T cellsRegulatory T cells 101How regulatory T cells mediate tolerance ?Modelling T cell population dynamicsOrdinary differential equations ··························· CRMWhat makes a T cell be a regulatory T cell ?Modelling gene regulatory networks and T cell differentiationLogical network formalism ······················ Th cell plasticityIf regulatory T cells are plastic how can tolerance be robust ?Multiscale modelling of cellular and supracellular networksAgent-based stochastic simulations
    10. 10. What does the immune system do in the vertebrate organism?
    11. 11. Fighting infection
    12. 12. Fighting infectionAssimilatingintestinal flora
    13. 13. Fighting infectionAssimilatingintestinal flora Rejecting cancer cells
    14. 14. Fighting infectionAssimilatingintestinal flora House keeping Rejecting cancer cells
    15. 15. Homeostasis Fighting infection and RegulationAssimilatingintestinal flora House keeping Rejecting cancer cells
    16. 16. Homeostasis Fighting infection and RegulationAssimilatingintestinal flora House keeping Rejecting cancer cells http://www.sciencemuseum.org.uk/exhibitions/lifecycle/116.asp http://ww.grc.org/Graphics/ programs/2003/cells3.jpg http://www.leukemia-web.org/images/cells.jpg
    17. 17. Failure of homeostasis and regulation unleashes pathologic autoimmunity
    18. 18. Failure of homeostasis and regulation unleashes pathologic autoimmunity Rheumatoid arthritis Type I diabetes Multiple sclerosis IPEX sindrome Cortesy: Magda Carneiro-Sampaio, São Paulo
    19. 19. From: Jean-François Bach, New England J Med
    20. 20. “In general, the management of human systemicautoimmune disease is empirical and unsatisfactory. For themost part, broadly immunosuppressive drugs, such ascorticosteroids, are used in a wide variety of severeautoimmune and inflammatory disorders (…)” – Philipe Cohen In: Fundamental Immunology (Ed. W. Paul)
    21. 21. Clonal selection theory Stem CellJerne, 1953Burnet, 1957 G.O.D. Ag A 1 2 3 4 ... 111 112 ... 623 ... 1245 ... n Ag B 1 2 3 4 ... 111 112 ... 623 ... 1245 ... n 111 111 1245 1245 111 111 111 111 1245 1245 1245 1245
    22. 22. CTL CTL CTL CTL CTL CTL TH CTLAntigen TH TH TH TH TH TH TH B B B B B B B TH
    23. 23. CTL CTL CTL CTL CTL CTL TH CTLAntigen TH TH TH TH TH TH TH B B B B B B B TH
    24. 24. CTL CTL CTL CTL CTL CTL TH CTLAntigen TH TH TH TH TH TH TH B B B B B B B TH
    25. 25. CTL CTL CTL CTL CTL CTL TH CTLAntigen TH TH TH “Self” tolerance by deletion TH TH TH TH B B B B B B B TH
    26. 26. CTL CTL CTL CTL CTL CTL TH CTLAntigen TH TH TH TH TH TH TH B B B B B B B TH
    27. 27. Reductionist molecular biology approach to Immunology
    28. 28. TOLERANCE = absence of clonal expansion = CLONAL DELETION Therapy of autoimmune diseases should aim at “deleting” autoreactive cells or clonesIn the absence of clonal-specific therapies: kill them all !!!
    29. 29. Is there any hope ?
    30. 30. Tolerance is mediated by regulatory T cellsMason-Sakaguchi WT
    31. 31. Tolerance is mediated by regulatory T cellsMason-Sakaguchi CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT
    32. 32. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT
    33. 33. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT
    34. 34. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT CD25+CD4+T cells R R R R R R R R (Regulatory T cells, TR, R)
    35. 35. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT CD25+CD4+T cells R R R R R R R R (Regulatory T cells, TR, R)
    36. 36. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT CD25+CD4+T cells R R R R R Healthy R R R (Regulatory T cells, TR, R)
    37. 37. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T (Effector T cells, TE, E) WT CD25+CD4+T cells R R R R R Healthy R R R (Regulatory T cells, TR, R)
    38. 38. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T AID (Effector T cells, TE, E) or Healthy WT CD25+CD4+T cells R R R R R Healthy R R R (Regulatory T cells, TR, R)
    39. 39. Tolerance is mediated by regulatory T cellsMason-Sakaguchi “empty” rag-/- AID CD25- CD4+ T cells E E E T E T T T T AID (Effector T cells, TE, E) or Healthy WT CD25+CD4+T cells R R R R R Healthy R R R (Regulatory T cells, TR, R)
    40. 40. Tolerance is mediated by regulatory T cells CTL CTL CTL CTL CTL CTL TH CTLSelfAntigen TH TH TH TH TH TH TH TH B B B B B B TH B
    41. 41. TOLERANCE = absence of clonal expansion = control by regulatory T cells Therapy of autoimmune diseases should aim at stimulating autoreactive regulatory T cells or clones
    42. 42. … BUT …there are many open questions
    43. 43. CD25+CD4+T cells R R R R R R R R (Regulatory T cells, TR, R)
    44. 44. What makes a T cellbe a regulatory T cell ? CD25+CD4+T cells R R R R R R R R (Regulatory T cells, TR, R)
    45. 45. What makes a T cell be a regulatory T cell ? CD25+CD4+T cells R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R)
    46. 46. What makes a T cell be a regulatory T cell ? CD25+CD4+T cells R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they prevent autoimmune diseases ?
    47. 47. What makes a T cell be a regulatory T cell ? CD25+CD4+T cells R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they allow efficient immune responses ? How do they prevent autoimmune diseases ?
    48. 48. What makes a T cell be a regulatory T cell ? How many and how CD25+CD4+T cells diverse are they ? R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they allow efficient immune responses ? How do they prevent autoimmune diseases ?
    49. 49. How does their repertoire What makes a T cell compare to that of other T be a regulatory T cell ? cells ? How many and how CD25+CD4+T cells diverse are they ? R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they allow efficient immune responses ? How do they prevent autoimmune diseases ?
    50. 50. Balance between regulatory and effector T cell subpopulations
    51. 51. Is it that simple ?
    52. 52. Is it that simple ?“Everything should be made as simple as possible, But not simpler.” Albert Einstein, XX century
    53. 53. http://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
    54. 54. http://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
    55. 55. http://www.sewingmachines.us/sewing-machine-636.jpghttp://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
    56. 56. http://www.sewingmachines.us/sewing-machine-636.jpg http://www.roselabiche.com/blog/index.php?2007/11http://www.medscape.com/content/2004/00/46/84/468446/468446_fig.html
    57. 57. http://web.mit.edu/2.972/www/reports/sewing_machine/a-sewing_machine.gif
    58. 58. Cell population dynamics
    59. 59. J. theor. Biol. (2000) 207, 231}254 doi:10.1006/jtbi.2000.2169, available online at http://www.idealibrary.com on Modelling T-cell-Mediated Suppression Dependent on Interactions in Multicellular Conjugates KALET LEON*-?, ROLANDO PEREZ*, AGUSTIN LAGE* D D AND JORGE CARNEIRO- MODELLING T LYMPHOCYTE LINKED SUPPRESSION 249 *Centro de ImmunolognH a Molecular, P.O. Box 16040, Habana 11600, Cuba and -Instituto Gulbenkian de Ciencia, Apartado 14, 2781-901, Oeiras, Portugal ore than two cell types with the alternative mechanisms of linked sup-mechanisms can be speci- (Received on 7 February 2000, Accepted in revised form onreported 2000) pression. Overall, the modelling results 10 Augustsetting of the interaction here and the whole set of observations that we the consequences of each discussed would strongly favour two candidate Tolerance to peripheral body antigens involves multiple mechanisms, namely T-cell-mediatedable 1). The application of suppression of potentially autoimmuneare Recent in vivo and in vitro evidence indicates that mechanisms. These cells. the ones that are trans- regulatory T cells suppress the response of e!ector T cells by a mechanism that requires the tions other than the cur- lated by the "nal model: regulatory T cells inhibit simultaneous conjugation of regulatory and e!ector T cells with the same antigen-presentingminant tolerance can be (APC). Despite this strong requirement, it is not yet clearwhile theywhile both cells are cell the proliferation of e!ector cells what happens are conjugated. Several hypotheses are discussed in the literature. Suppression may result from For example, it was competition of regulatory and e!ectoracells for activation resources on the APC; simple nevertheless dependent on growth factor that the the interaction between regulatory T cellsproduce; an inhibitory signal tocells inhibit the same conjugate; or latter may deliver or regulatory e!ector T cells in the ex- e!ector T cells may acquire the regulatory phenotype during their interaction with regulatory Ls does not involve thecells. The present article tries to further our understanding of T-cell-mediated suppression, T pansion of the population of e!ector cells because they convertnumber of multicellular conjugates of T propose the "rst generalns between the two cells to narrow-downthe formation of to the regulatoryWe cells and APCs. Using this and formalism describing the them candidate mechanisms. phenotype. formalism we derive three particularor both may be operative in of T-cell- resenting cell, as classi- Either mechanism models, representing alternative mechanisms mediated suppression. For each model, we make phase plane and bifurcation analysis, and son & OMalley, 1987; vivo, maybe even dependent on with the history of identify their pros and cons in terms of the relationshipthe life large body of experimentalhat the APC may act as observations on T-cell-mediated Modigliani et al.that accounting for the quantitative the e!ector cells. suppression. We argue (1996b) actually details of adoptive transfers of tolerance requires models with bistable regimes in which eithernnett et al., 1998; Ridge regulatory cells or e!ectors cells dominate the steady cellsFrom this thymic conclude demonstrated that regulatory state. from analysis, wer et al., 1998). The formal- cells actively inhibit mechanism of T-cell-mediated suppression the maintenance of the that the most plausible T epithelium the growth of can both suppressrequires re- regulatory chimeras e!ector T cells, and that the that
    60. 60. Modelling T cell population dynamicsnet growth = influx + interaction-dependent — death growth dTi = i + ↵i (T, A, m, k) · Ti · Ti dt
    61. 61. Modelling T cell population dynamicsnet growth = influx + interaction-dependent — death growth dTi = i + ↵i (T, A, m, k) · Ti · Ti dt
    62. 62. Modelling T cell population dynamicsnet growth = influx + interaction-dependent — death growth dTi = i + ↵i (T, A, m, k) · Ti · Ti dt
    63. 63. Modelling T cell population dynamicsnet growth = influx + interaction-dependent — death growth dTi = i + ↵i (T, A, m, k) · Ti · Ti dt
    64. 64. Modelling T cell population dynamicsnet growth = influx + interaction-dependent — death growth dTi = i + ↵i (T, A, m, k) · Ti · Ti dt How to choose appropriate functional forms for the interaction terms ?
    65. 65. Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction R T IL-X R R [Leon et al. J Theor Biol 2000; Carneiro et al. Immunol Rev 2007]
    66. 66. Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction R T IL-X R R [Leon et al. J Theor Biol 2000; Carneiro et al. Immunol Rev 2007]
    67. 67. Modelling T cell population dynamicsA taxonomy of putative mechanisms of cell-to-cell interaction R T IL-X R R CRM [Leon et al. J Theor Biol 2000; Carneiro et al. Immunol Rev 2007]
    68. 68. Modelling T cell population dynamics: the crossregulation model Interactive simulation
    69. 69. Quantitative assay for cell proliferation+CFSE Nº Cells Log FL1-H Log Intensity of CFSE staining [Leon et al. J.Theor.Biol. 2004]
    70. 70. Putting the CRM to the test + anti-CD3 antibody APCs Cell Cycle R R R R E R R R R R R R RB6 Thy1.2 Analysis CD25+CD4+Thy1.2+ 3 day culture E E E E E E E E E E E E E E E E E EB6 congenic Thy1.1 CD25-CD4+Thy1.1+ [Carneiro et al. Immuno. Rev. 2007]
    71. 71. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ ? ? 3 day culture E E E E E E E E E + + anti-CD3100:0 N.D. E E E E E E antibody E E E NDy1.1 CD25-CD4+Thy1.1+ 80:20 47:53 Cell Cycle R R E R R R R Analysis.2+ + anti-CD3 antibody 50:50 24:76 APCs 3 day culture E E E E E E E + E + anti-CD30:100 N.D. Cycle antibody E Cell R R R R E R R R R R R R R ND Analysis1.1+ CD25+CD4+Thy1.2+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E E E E E E Cell Cycle R E R E E E E R R R R CD25-CD4+Thy1.1+ Analysis et al. Immuno. Rev. 2007] [Carneiro.2+
    72. 72. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ ? 3 day culture E E E E E E E E E + + anti-CD3100:0 N.D. E E E E E E antibody E E E NDy1.1 CD25-CD4+Thy1.1+ 80:20 47:53 Cell Cycle R R E R R R R Analysis.2+ + anti-CD3 antibody 50:50 24:76 APCs 3 day culture E E E E E E E + E + anti-CD30:100 N.D. Cycle antibody E Cell R R R R E R R R R R R R R ND Analysis1.1+ CD25+CD4+Thy1.2+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E E E E E E Cell Cycle R E R E E E E R R R R CD25-CD4+Thy1.1+ Analysis et al. Immuno. Rev. 2007] [Carneiro.2+
    73. 73. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ 3 day culture E E E E E E E E E + + anti-CD3100:0 N.D. E E E E E E antibody E E E NDy1.1 CD25-CD4+Thy1.1+ 80:20 47:53 Cell Cycle R R E R R R R Analysis.2+ + anti-CD3 antibody 50:50 24:76 APCs 3 day culture E E E E E E E + E + anti-CD30:100 N.D. Cycle antibody E Cell R R R R E R R R R R R R R ND Analysis1.1+ CD25+CD4+Thy1.2+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E E E E E E Cell Cycle R E R E E E E R R R R CD25-CD4+Thy1.1+ Analysis et al. Immuno. Rev. 2007] [Carneiro.2+
    74. 74. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ 3 day culture E E E E E E E E E + + anti-CD3100:0 N.D. E E E E E E antibody E E E NDy1.1 CD25-CD4+Thy1.1+ 80:20 47:53 Cell Cycle R R E R R R R Analysis.2+ + anti-CD3 antibody 50:50 24:76 ? ? APCs 3 day culture E E E E E E E + E + anti-CD30:100 N.D. antibody E Cell Cycle R R R R E R R R R R R R R ND Analysis1.1+ CD25+CD4+Thy1.2+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E E E E E E Cell Cycle R E R E E E E R R R R CD25-CD4+Thy1.1+ Analysis et al. Immuno. Rev. 2007] [Carneiro.2+
    75. 75. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ 3 day culture E E E E E E E E E + + anti-CD3100:0 N.D. E E E E E E antibody E E E NDy1.1 CD25-CD4+Thy1.1+ 80:20 47:53 Cell Cycle R R E R R R R Analysis.2+ + anti-CD3 antibody 50:50 24:76 APCs 3 day culture E E E E E E E + E + anti-CD30:100 N.D. Cycle antibody E Cell R R R R E R R R R R R R R ND Analysis1.1+ CD25+CD4+Thy1.2+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E E E E E E Cell Cycle R E R E E E E R R R R CD25-CD4+Thy1.1+ Analysis et al. Immuno. Rev. 2007] [Carneiro.2+
    76. 76. Putting the CRM to the test + anti-CD3 antibody APCs Proportions Effector Cells Regulatory Cells Thy1.1:Thy1.2 Thy1.1 Thy1.2 Cell Cycle R R R E R R R R R Day 0 Day 3 R R R R Analysis CD25+CD4+Thy1.2+ + anti-CD3 antibody 3 day culture APCsE EE EE E E E E + + anti-CD3100:0 N.D. antibody E E E E E E E E E NDy1.1 CD25-CD4+Thy1.1+ Cell Cycle R R R E R R R R R + anti-CD3 antibody ? ? R R R R AnalysisCD25+CD4+Thy1.2+ APCs 80:20 47:53 Cell Cycle R R E 3 day culture R R + + anti-CD3 antibody R ? ? + E E E E R E E E E Analysis Cell Cycle E E E E E E R E E E RE R E R R R R R R R R R.2+CD25-CD4+Thy1.1+Thy1.2 Analysis CD25+CD4+Thy1.2+ 50:50 24:76 3 day culture 3 day culture Cell Cycle R R EE E E E E E E E E E R E ER E E E E E E R E E E E E E E R E E Analysis 0:100 N.D.ongenic Thy1.1 ND CD25-CD4+Thy1.1++1.1+ 3 day culture Log FL1-H / CFSE intensity E E E E E E E E E [Carneiro et al. Immuno. Rev. 2007]+
    77. 77. Putting the CRM to the test Proportions Effector Cells Regulatory CellsThy1.1:Thy1.2 Thy1.1 Thy1.2Day 0 Day 3100:0 N.D. ND80:20 47:5350:50 24:760:100 N.D. ND Log FL1-H / CFSE intensity [Carneiro et al. Immuno. Rev. 2007]
    78. 78. Modelling T cell population dynamics: the crossregulation model R T IL-X R R CRM [Leon et al. J Theor Biol 2000; Carneiro et al. Immunol Rev 2007] [Carneiro et al. Immuno. Rev. 2007]
    79. 79. Modelling T cell population dynamics: the crossregulation model Regulatory T cell populations grow as a function of the effector T cells they suppress R R Leon et al. JTB (2000) R E E E 01 . Imm unol 20 iol 2 000 , J al. J Theor B eon et Thesis L alh o PhD sis , Caram hD The
    80. 80. the control of the insulin promoter. We had previously observedModelling T cell population dynamics: the crossregulation model Authorship note: Yenkel Grinberg-Bleyer and David Saadoun contributed equally to this work. Eliane Piaggio and Benoît L. Salomon are co–senior authors. that HA-specific Tregs (HA-Tregs) preferentially proliferated and expanded at days 5–7 after transfer in draining pancreatic LNs Conflict of interest: The authors have declared that no conflict of interest exists. (PLNs) of ins-HA homozygous mice (29). When we repeated the Citation for this article: J Clin Invest. 2010;120(12):4558–4568. doi:10.1172/JCI42945. experiment in ins-HA hemizygous recipients, which express lower The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 12 December 2010 Related Commentary, page 4190 Regulatory T cell populations grow as a function of the effector T cells they suppress Yenkel Grinberg-Bleyer,1,2,3 David Saadoun,1,2,3 Audrey Baeyens,1,2,3 Fabienne Billiard,1,2,3 Jérémie D. Goldstein,1,2,3 Sylvie Grégoire,1,2,3 Gaëlle H. Martin,1,2,3 Rima Elhage,1,2,3 Nicolas Derian,1,2,3 Wassila Carpentier,1,4 Gilles Marodon,1,2,3 David Klatzmann,1,2,3 R R Eliane Piaggio,1,2,3 and Benoît L. Salomon1,2,3 1Université Pierre et Marie Curie — Univ Paris 06, 2CNRS UMR 7211, 3INSERM U959, Paris, France. 4Plate-forme Post-Génomique P3S, Hôpital Pitié-Salpêtrière, Paris, France. Leon et al. JTB (2000) CD4+CD25+Foxp3+ Tregs play a major role in prevention of autoimmune diseases. The suppressive effect of Tregs on effector T cells (Teffs), the cells that can mediate autoimmunity, has been extensively studied. How- R E ever, the in vivo impact of Teff activation on Tregs during autoimmunity has not been explored. In this study, we have shown that CD4 + Teff activation strongly boosts the expansion and suppressive activity of Tregs. This helper function of CD4+ T cells, which we believe to be novel, was observed in the pancreas and draining lymph nodes in mouse recipients of islet-specific Teffs and Tregs. Its physiological impact was assessed in autoimmune diabetes. When islet-specific Teffs were transferred alone, they induced diabetes. Paradoxically, when the same Teffs were cotransferred with islet-specific Tregs, they induced disease protection by boost- E ing Treg expansion and suppressive function. RNA microarray analyses suggested that TNF family members were involved in the Teff-mediated Treg boost. In vivo experiments showed that this Treg boost was partially E dependent on TNF but not on IL-2. This feedback regulatory loop between Teffs and Tregs may be critical to preventing or limiting the development of autoimmune diseases. bers of mature DCs in inflamed tissues may favor the activation of 01 unol 20 The peripheral T cell repertoire of any individual contains autoreac- autoreactive Tregs (21–23), which would then turn on their sup- tive T cells specific for a variety of self antigens (1). Their activation pressive activity and exert bystander suppression (24, 25). Thus, during an autoimmune process, there is a local enrichment 00 , J . Imm could induce an autoimmune process, eventually leading to an auto- Bi ofl 2 0 of both autoreactive Teffs and Tregs. Since heefficacy o Treg- immune disease. Severe and prolonged inflammation in a tissue may J T the orbetween acti- mediated suppression depends onal. equilibrium eon et the factor that could tip this Thesis o PhD lead to the activation of pathological autoreactive T cells by several L Tregs (26), any mechanisms (2, 3). At the site of inflammation or in draining LNs, vated Teffs and activated balance to one side or the other could then determine thes, Ca ramalh tissue damage results in an enhanced presentation of autoantigens hD Th esi outcome
    81. 81. How does their repertoire What makes a T cell compare to that of other T be a regulatory T cell ? cells ? How many and how CD25+CD4+T cells diverse are they ? R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they allow efficient immune responses ? How do they prevent autoimmune diseases ?
    82. 82. How does their repertoire What makes a T cell compare to that of other T be a regulatory T cell ? cells ? How many and how CD25+CD4+T cells diverse are they ? R RHow do they interact R R R R R R with other cells ? (Regulatory T cells, TR, R) How do they allow efficient immune responses ? How do they prevent autoimmune diseases ?

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