immunological tolerance can be divided into two parts. they are central tolerance and peripheral tolerance. this slide contains information on development of central tolerance which include both B cell and T cell central tolerance.
Presented by Somen Kumar MistriDepartment of Microbiology University of Dhaka Dhaka, Bangladesh
How does the immune system provide a high degree of sensitivity and specificity to the broad array of pathogens without attacking self? How does a T-cell know whether to be CD4+ T-cell or CD8+ T-cell? How does T-cells come in contact with all the self antigens in thymus? What is the role of IgD in the development of B-cell tolerance?
Central Tolerance Thymic B-cell tolerancetolerance to to self antigenself antigen (In Bone Marrow) (In Thymus)
Thymus - Site of T-cell Maturation Cortex Medulla
In a young mouse , the thymus contains around 108 to 2×108 T-cells. Each day about 5×107 new T-cells are generated. Only 106 to 2×106 (Roughly 2 - 4%) of these will leave the thymus each day as mature T-cells So approximately 98% of T-cells that develop in thymus also die within the thymus. Death is usually by apoptosis.
Positive Selection Recognition of Self -MHCNegative Selection Avoid strong binding to self antigen
Particular combinations of cell surface proteins can be used as markers for T-cells at different stages of differentiation. Two distinct lineages of T-cell: α:β and γ:δ. When progenitor cells first enter the thymus from bone marrow, they lack most of the surface molecules characteristic of mature T-cells. Their TCR genes are not rearranged at that time. In fact, proteins such as RAG1 and RAG2 (Recombination Activating Gene ) are not expressed that are required for rearrangement. At first T-cells do not contain : CD3 : TCR complex CD4 or CD8
Once DN1 cells encounter the thymic environment , they begin to proliferate and express CD25. During DN2 stage , rearrangement of the genes for TCR γ , δ , β chains begins. RAG expression gets turned on at this stage. Cells destined to become γδ T-cells (˂ 5% of mature lymphocytes) diverge at the transition between DN2 and DN3. After DN3 stage DN4 stage comes. RAG expression stops here and proliferation of DN4 cells occurs.
Formation of pre-TCR activates a signal transduction pathway that has several consequences : Indicates that a cell has made a productive TCR β-chain rearrangement and signals its further proliferation and maturation. Suppresses further rearrangement of TCR β-chain genes, resulting in allelic exclusion. Renders the cell permissive for rearrangement of the TCR α-chain. Induces the developmental progression to the CD4+ 8+ double positive (DP) state.
Newly formed DP cells reactivate RAG genes allowing rearrangement of the α-chain. Pairing of α and β-chains allow T-cells to recognize a wide range of antigens (Both self and foreign). At this point positive selection occurs. Cells that recognize MHC with moderate affinity on cortical epithelial cells survive. Cells whose TCR interacts with MHC class I becomes CD4+ T-cell (SP). Cells whose TCR interacts with MHC class II becomes CD8+ T-cells(SP). Cells whose TCR fails to engage either a class I or class II MHC molecule undergo programmed cell death.
Proliferatio n Positive selectio n Negative Selection•Positive selection involves recognition of self MHC at cortical epithelial cells.Mechanism not really known.•Negative selection predominantly in medulla (Medullary epithelial cells)
Positive selection for thymocytes bearing receptors capable ofbinding self-MHC molecules, which results in MHCrestriction. Cells that fail positive selection are eliminatedwithin the thymus by apoptosis.Negative selection that eliminates T-cells bearing high affinityreceptors for self-MHC molecules alone or self antigenpresented by self-MHC, which results in self-tolerance.
POSITIVE NEGATIVE SELECTION SELECTION APC APC APC MHC MHC MHC Self antige TCR n TCR TCR T-cell T-cell T-cellBinding of TCR and MHC Weak binding of TCR Strong binding of(weak), results in positive and MHC-Peptide TCR and MHC- selection of T-cells complex :T-cell is peptide complex : T- positively selected cell is negatively selected
Engagement of TCR by the MHC-peptide complex on some type of antigen presenting cell underlies both positive and negative selection. Positive and negative selection may occur at low and high degrees of TCR ligation, respectively. Experiments show that the same peptide will induce positive selection at low concentration and negative selection at high concentration. This has led to the avidity model, which postulates that a functionally low avidity interaction between T-cell and peptide- MHC involving a relatively low number of TCRs will positively select Double positive (DP) CD4+8+ thymocytes, while a high avidity interaction will lead to clonal deletion. The overall avidity of the T-cell interaction is a function of : Ligand Density TCR Density Affinity
It is postulated that a low avidity interaction between the T-cell andAPC will give positive selection and that high avidity will givedeletion.* Refers to affinity of peptide for the MHC or of the MHC-peptidecomplex for the TCR
The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. AIRE is a transcription factor expressed in the medulla of the thymus and controls the mechanism that prevents the immune system from attacking the body itself. AIRE allows endothelial cells in thymus as well as dendritic cells to express other proteins that they normally do not express. Due to the presence of AIRE medullary epithelial cells as well as dendritic cells present self peptides in low amount to T-cells. This serves the negative selection purpose. Mutation in AIRE results in Autoimmune Polyendocrinopathy– Candidiasis–Ectodermal Dystrophy (APECED).
B-cell development shows similar features to T-cell development, but takes place largely in the bone marrow. Checkpoints in B-cell development include : Successful expression of Igα and Igβ in late pro-B cells. Successful rearrangement at the heavy chain locus in pre B-cells. Successful rearrangement at the light chain locus and receptor editing. Mature B-cells express IgD at higher levels than IgM. Self tolerance begins when IgM first appears at the surface of the developing cell.
Expression of IgD is an important checkpoint in terms of eliminating self reactive B-cells. Normally in a mature B-cell, when Antigen binds to mIg of that B-cell, it turns the B-cell on. However, before IgD is expressed, if antigen (Self) binds to mIg then the B-cell gets turned off. Further development of that B-cell does not occur, but light chain rearrangement can continue.
If in bone marrow,IgM binds to a non-cross linking selfmolecule it can notgive strong signal tothe B-cell to die,instead it generates aB-cell that may not beas responsive orclonally ignorant.
Allowing light chain rearrangement to continue among immature cells permits the B-cell to edit its receptor and rescue potentially autoreactive cells from inevitable death. Thus by changing the light chain, a self reactive B-cell can be converted to a non-self reactive one. After making a new light chain, the mIgM is again tested to see if this is also self reactive. If the heavy chains association with antigen is very strong, then light chain rearrangement alone can not alter self reactivity. Ultimately that B-cell would not be allowed to leave the bone marrow.
If cross linking occurs, but leastsufficiently to produce strongsignal, the B-cell does not die byapoptosis. It migrates to the periphery andactually become anergic B-cells. Even though they are selfreactive they won’t makeantibodies. Therefore they won’tcause any kind of autoimmunediseases.