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Allogeneicity and Immunogenicity of Stem Cell Therapy : a cardiovascular focus
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Allogeneicity and Immunogenicity of Stem Cell Therapy : a cardiovascular focus

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On March 12th 2013 took place at Vall d’Hebron Institut de Recerca (VHIR) the seminar ‘Allogeneicity and Immunogenicity of Stem Cell Therapy: a cardiovascular focus’, conducted by Pr. Dominique …

On March 12th 2013 took place at Vall d’Hebron Institut de Recerca (VHIR) the seminar ‘Allogeneicity and Immunogenicity of Stem Cell Therapy: a cardiovascular focus’, conducted by Pr. Dominique Charron, MD, PhD, Professor of Medicine, Immunology at the University of Paris and Chairman of the Department of Immunology and Histocompatibility at Hospital Saint Louis in Paris.

Research on stem cell therapies for regenerative medicine is progressing rapidly. Although the use of autologous stem cells is a tempting choice, there are several instances in which they are either defective or not available in due time. Allogenic stem cells derived from healthy donors presents a promising alternative. Whether autologous or allogenic, recent advances have proven that stem cells are not as immune privileged as they were thought. Therefore understanding the interactions of these cells with the recipient immune system is paramount to their clinical application. Transplantation of stem cells induces humoral as well as cellular immune response.

The research group of Pr. Dominique Charron investigated the immune characteristics of human cardiac stem/progenitor cells lines in term of major histocompatibility complex (MHC) expression, allogenicity and immuno modulatory properties. By using an experimental model of allogeneic stimulation, they demonstrate that, whether under inflammatory conditions or not, human cardiac progenitor cells (hCPC) do not trigger conventional allogeneic T helper cells type responses but instead induce proliferation and selective expansion of suppressive of regulatory T cells (Treg). Thus, hCPC in allogeneic settings acquire the capacity to down-regulate an ongoing immune response.

For stem cell therapy to move to the clinics, immunological barriers should be pragmatically managed. It could be recommended to minimize immunogenetic differences between stem cell and recipient, assay the immunization status of the recipient prior to stem cell injection, and monitor both allogenic and autoimmunity post stem cell transplantation. Integrating the unique immunobiology of stem cell with the patient immune status is key to successful translation to the clinics.

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  • 1. VHIR CONFERENCE 2013 BARCELONA «Allogenicity & Immunogenicity of Stem Cell Therapy : a Cardiovascular Focus » DOMINIQUE CHARRON,MD,PhD Dominique.Charron @ sls.aphp.fr Laboratoire « Jean Dausset » & INSERM U 940Hopital Saint-Louis ,IUH ,Université Paris-Diderot , France
  • 2. IMMUNOGENETICS & MEDICINE XXth Century XXth CenturyHLA,, MHC ,Cytokines,Receptors….HLA MHC ,Cytokines,Receptors…. …TRANSPLANTATION, AUTOIMMUNITY,INFECTIONS …TRANSPLANTATION, AUTOIMMUNITY,INFECTIONS XXI st Century HLA & MEDICINE (Schizophrenia,Parkinson … ) IMMUNO PHARMACOGENETICS (Abacavir,Carbamazepin ,Allopurinol…) REGENERATIVE MEDICINE/CELL & IMMUNO THERAPIES TOWARD « SYSTEMS BIOLOGY/SYSTEMS MEDICINE »
  • 3. MHC / HLA Complete sequence and gene mapHLA CONSORTIUM – Nature 11/1999
  • 4. # HLA Alleles
  • 5. HLA DIVERSITY = BIOLOGICAL SELFHLA DIVERSITY = BIOLOGICAL SELF 2013 : 8496 ALLELES WE ARE THE LIMIT
  • 6. Pathways of AllorecognitionPathways of Allorecognition Tc Th Cytotoxic T-cell Helper T-cell Allogeneic (Donor) Cell Allo MHC molecules MHC or other molecules from the Donor are are shed recognized by Host T- taken up and Tc Class I Class II processed by host APC cells Cytotoxic T-cell Allogeneic (Donor) APC (stimulator) Direct allorecognition Direct allorecognition Th Helper T-cell Host APC (recipient) Peptide derived from allo molecules presented on host MHC Indirect allorecognition Indirect allorecognition to Host T-cellsImmune Cell Stem Cell
  • 7. Allo Recognition/Activation Pathways Direct vs Indirect Recognition phase APC Donor Recipient HLA-peptide Donor -Donor Recipient - Donor Pre-existing T cell frequency 1/103 – 1/104 1/105 – 1/106 Immediate Response Effector phase Cytokine production (inflammatory response) + ++Th B cell activation (Ab production) - +++ Direct cytotoxicityTc (of donor tissue) ++ - Duration of response Short lived long lived (donor APC) (donor peptide) Outcome Acute Rejection Chronic Rejection
  • 8. CONSEQUENCES OF HLA HISTO- INCOMPATIBILITY INTRANSPLANTATION ……2012 T CELL MEDIATED : REJECTION (ORGANS) & GVH(HSCT) ANTI HLA ANTIBODY MEDIATED: CHRONIC REJECTION(ORGANS) & NO ENGRAFTMENT (HSCT) 2013 CHANGE OF PARADIGM
  • 9. Antibody-mediated vascular rejection of kidney allografts:a population-based studyCarmen Lefaucheur*, Alexandre Loupy*, Dewi Vernerey, Jean-Paul Duong-Van-Huyen, CarolineSuberbielle, Dany Anglicheau, Jérôme Vérine, Thibaut Beuscart, Dominique Nochy, Patrick Bruneval, Dominique Charron, Michel Delahousse, Jean-PhilippeEmpana, Gary S Hill, Denis Glotz, Christophe Legendre, Xavier JouvenLANCET Nov 23,2012
  • 10. Population based study 2079 patients(nck/sls)+ 602validation samples(foch) 302 biopsy proven rejection (1998-2008) CINICAL, HISTO PATHOLOGICAL(including C4d)& IMMUNOLOGICAL(DSA) DATA Hierarchical cluster analysis unsupervised principal component 4 patterns of rejectionTCMR/V+ :T cell mediated rejection (26 9 °/°)ABMR/V+ :Antibody mediated rejection(64 21°/°)TCMR/V- : T cell mediated rejection without vasculitis(139 46°/°)ABMR/V- : Antibody mediated rejection without vasculitis(73 24°/°)
  • 11. PATHOLOGICAL & IMMUNOLOGICAL PHENOTYPES OF THE 4 REJECTION PATTERNS
  • 12. Cellular (Tcell) rejection Antibody mediated rejection TCMR V - ABMR V -Endarteritis --Endarteritis + ABMR V + TCMRV+
  • 13. GRAFT SURVIVAL IN THE 4 REJECTION PHENOTYPES ABMR V+
  • 14. HLA, MHC AND MUCH MORE….HLA, MHC AND MUCH MORE…. …TRANSPLANTATION, AUTOIMMUNITY AND MUCH MORE …TRANSPLANTATION, AUTOIMMUNITY AND MUCH MORE HLA in MEDICINE IMMUNOPHARMACOGENETICS REGENERATIVE MEDICINE SYSTEMS BIOLOGY
  • 15. REGENERATIVE MEDICINE AND TRANSPLANTATION BENEFITS BENEFITS PLURI //MULTIPOTENCY PLURI MULTIPOTENCY SELF RENEWAL SELF RENEWAL IN VITRO SPECIFIC DIFFERENCIATION IN VITRO SPECIFIC DIFFERENCIATION IMMUNE PRIVILEGE ? IMMUNE PRIVILEGE ? LIMITS OF IN VIVO ENGRAFTMENT AND FUNCTIONALITY LIMITS OF IN VIVO ENGRAFTMENT AND FUNCTIONALITYIMMUNOGENICITY/ALLOGENICITY/REJECTION/AUTOIMMUNITY ? IMMUNOGENICITY/ALLOGENICITY/REJECTION/AUTOIMMUNITY ? DISPONIBILITY – TIMELINE  DISPONIBILITY – TIMELINE AGING  AGING SAFETY  SAFETY ETHICAL – REGULATORY ISSUES  ETHICAL – REGULATORY ISSUES
  • 16. THE IMMUNITY FACTORS IN REGENERATIVE CELL THERAPIES  THE IMMUNOGENETIC FACTOR: ALLOGENICITY HLA, MHC and Much More….  THE IMMUNE EFFECTORS: DIRECT vs INDIRECT PATHWAYS OF ALLO RECOGNITION Cells, Mediators and Allo Antibodies...  THE AGING FACTOR: IMMUNO SENESCENCETowards an IMMUNOLOGICALLY EDUCATED CHOICE OFSCsImmune Cell Stem Cell
  • 17. 2002 -2008 ALLOGENEIC STEM CELLS ARE NOT ALLOGENEIC STEM CELLS ARE NOT IMMUNO PRIVILEGED IMMUNO PRIVILEGED MHC EXPRESSION IMMUNOGENICITY INCREASES UPON DIFFERENCIATION IN VIVO REJECTIONImmune Cell 3 SUPPORTING PAPERS Stem Cell
  • 18. CHARACTERIZATION OF THE EXPRESSION OF MHC PROTEINS IN HUMAN EMBRYONIC STEM CELLS M. DRUKKER, G. KATZ, A. URBACH, M. SCHULDINER, G. MARKEL, J. ITSKOVITZ-ELDOR, B. REUBINOFF, O. MANDELBOIM, N. BENVENISTY PNAS, 2002, 99:9864 UNDIFFERENTIATED DIFFERENTIATED In vitro In vivo β2m Counts HLA-I 721/HLA-G HLA-IIImmune Cell Stem Cell Fluorescence intensity
  • 19. IFN-γ induction of MHC-I in human ES cells is dose and IFN-γ induction of MHC-I in human ES cells is dose and time dependent time dependent
  • 20. Embryonic Stem Cell Immunogenicity Increases Upon Differentiation After Transplantation Into Ischemic Myocardium R-J Swijnenburg, M. Tanaka, H. Vogel, J. Baker,T. Kofidis, F. Gunawan, D.R. Lebl, A.D. Caffarelli, J.L. de Bruin, E.V. Fedoseyeva, R.C. Robbins Circulation. 2005;112:I-166-I-172 Graft infiltration of immune cells after transplantation of in vivo differentiated ESCsT cells B cells
  • 21. 2O10 DIFFERENCIATION OF ALLOGENEIC MESENCHYMAL STEM CELLS INDUCES IMMUNOGENICITY & LIMITS THEIR LONG-TERM BENEFITS FOR MYOCARDIAL REPAIR Xi-Ping Huang & coll Circulation .2010 ;122:2419-242 • Wistar and lewis rats • MSCs untreated vs MSCs cultured with 5-azacytidine(to induce myogenic differentiation) Flow cytometric & mRNA evaluation of MHC Ia,II and CD86 is increased by >30% upon differentiation While MHC Ib is decreased -------GFP+ MSCs Implanted into the infarcted myocardium 3 weeks after MI express low level of MHC Ia when undifferenciated(alpha-SMA-) at day seven & high level of MHC Ia when differenciated(alpha-SMA+) at Day 14(differenciated) ------ Implanted Allogeneic MSCs induce a local immune reaction after 7 days and are not detected in situ after 5 weeks -------Allogeneic MSCs restore cardiac function as effectively as Syngeneic MSCs for 3 months but not 6 monts after implantation While immunoprivileged in their undifferenciated state MSCs become immunogenic in vitro & in vivo when differenciated (biphasic immune response)
  • 22. ALLOGENICITY/IMMUNOGENI CITY & IMMUNOMODULATORY PROPERTIES of HUMAN CARDIAC PROGENITOR/STEM CELLS
  • 23. Human Cardiac Stem/Progenitor Cells Characterization •Cells from Different donors : Endomyocardic biopsy Collagenase Treatment ckit purification/enrichment • Pluripotency Transcription factors STEM CELL MARKERS hCPC Cardiac differenciation hCPC Cardiac differenciation potency(in vitro) potency(in vitro) Cardiomyocytes Cardiomyocytes• CARDIAC LINEAGE SC MARKERS Endothelial cells Endothelial cells Smooth muscle cells Smooth muscle cells Nadal-Ginard B et al. Resident human cardiac stem cells: role in cardiac cellular homeostasis and potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med 2006;3
  • 24. Immunology of Human Cardiac Stem/Progenitor Cells for cardiac repair 3% O2 Non- Inflammatory Inflammatory (IFNγ 72h)  IL-10 producing CD4+ cells  low immunogenic profileLauden L. et al, Circ Res, 2013
  • 25. Immunology of Human Cardiac Stem/Progenitor Cells for cardiac repairhCPC are Immuno-modulators  Down-regulate an ongoing immune response (CD4+, CD8+, IFNγ, IL-2)  More potent within inflammatory conditions Lauden L. et al, Circ Res, 2013
  • 26. hCPC & Regulatory T cellsALLOGENEIC hCPC ACTIVATE AND EXPAND T regsALLOGENEIC hCPC ACTIVATE AND EXPAND T regs
  • 27. Characterisation of hCPC activated Regulatory T cells HLA DR+ PD-1+ Regulatory TTCells HLA DR+ PD-1+ Regulatory Cells
  • 28. PD-L1 (1) anti-PD-L1 anti-PD-L1Inhibition of Treg expansion Inhibition of the Immunomodulatory effect
  • 29. PD-L1 (2) siRNA Inhibition siRNA InhibitionPD-L1 is implicated in Treg ss activation & immunomodulation by hCPCs PD-L1 is implicated in Treg activation & immunomodulation by hCPCs
  • 30. Conclusions••hCPC are attractive for clinical Translation hCPC are attractive for clinical Translation -- Low immunogenic profile( No immediate rejection ? )) Low immunogenic profile( No immediate rejection ? --Maintainanceof immunologic properties under inflammatory Maintainance of immunologic properties under inflammatory conditions conditions --Immunomodulatoryproperties Immunomodulatory properties••PD-L1/PD-1 orchestrate immunologic properties of hCPC PD-L1/PD-1 orchestrate immunologic properties of hCPC --Treg generation Treg generation --hCPC-induced immunomodulation hCPC-induced immunomodulation••Allogenic-driven benefit? Allogenic-driven benefit? --hCPC-induced allogenic response is biased towards Treg hCPC-induced allogenic response is biased towards Treg --Immune properties of hCPC are controlled by PD-L1/PD-1 pathway Immune properties of hCPC are controlled by PD-L1/PD-1 pathway
  • 31. ALLOGENICITY Beneficial Detrimental Allogenic-driven-risk versus Allogenic-driven-benefit Immune behavior of other stem cells (iPSC and ESC- and iPSC-derived progenitors) Regulation of MHC expression in stem cells and their progenitors Reactivity with allo-antibodies (risk or benefit?) Markers of selection (PD-L1?) Immunologically educated choice of ALLOGENIC STEM CELLS Optimization of ALLOGENIC STEM CELLS for use in Regenerative Medicine
  • 32. 2002 - 2010  Allogeneic ESCs are Immunogenic : alloimmunity 2010 - 2012 Reprogrammed iPSCs are immunogenic :autoimmunity Gene Transduced cells are immunogenic: autoimmunity Allogeneic MSCs are immunogenic:alloimmunity Endomyocardiac stem cells are allogeneic and ImmunomodulatoryImmune Cell Stem Cell
  • 33. • IMMUNOGENETIC SELECTION/BANK OF SC/MATCHING• INDUCTION OF TOLERANCE• IMMUNOMODULATION• IMMUNOMONITORING
  • 34. Immunogenetic selection– HLA MATCHING - REDUCING HLA MISMATCHING • Pre TX Screening for anti HLA Characterizing anti HLA specificities(SAB) + MIC-A? C1Q? C4d? Cross-Matching Post TX monitoring anti HLA antibodies STEM CELL BANKING Autologous Cells (anticipatory) Cells derived from Homozygous individuals (frequent haplotypes) Allogenic Cells
  • 35. A transplant immunologist point of view• Minimize immunogenetic differences• Assay the immunization status of the recipient prior to SCT injection• Monitor allogenic & autoimmunity post SCT• Be pragmatic (…immunosupression) and• Utopic( …hope for tolerance one day )
  • 36. Acknowledgement Reem AL DACCAK Hopital Saint-Louis Khaoussou Sylla UMRS940 Isabelle Martins Kiran Ramgolam Laura Lauden IC Wahid Boukouaci TC&SC Luis Borlado Miguel Mulet Parada Ryad Tamouza Coretherapix (Madrid, Spain) Caroline Suberbielle Bernardo Nadal-Ginard Georgina Ellison Pascale Loiseau Liverpool John Moores University Emeline Masson (Liverpool, UK) FP7 – CARE-MI Consortium , INSERM; EU FP7 – CARE-MI
  • 37. HLA IMMUNITY & STEM CELL THERAPY 2013 NOW THIS IS NOT THE END IT IS NOT EVEN THE BEGINNING OF THE END BUT IT IS PERHAPS, THE END OF THE BEGINNING… Hopital Saint-Louis
  • 38. Immune phenotype: HLA expression Immune phenotype: HLA expression HLA-class I HLA-DR HLA-DQ HLA-DP hCSC (850) (7) (0) (18) CD80 CD86 CD40 (0) (33) (0)hCSC-IFNγ HLA-class HLA-DR HLA- HLA- I (405) DQ DP (18400) (540) (540) MHC II… induction only seen when cells are maintained under hypoxia (3% O2) physiological inflammatory conditions…?
  • 39. hCPC IMMUNOPHENOTYPERESTING & UNDER INFLAMMATORY CONDITION (INF g treated) No change in morphology & pulripotency markers after IFNγ treatmenthCPC display a low immunogenic profile Induction of HLA-class II + INF G Increase expression of HLA-class I & PD-L1
  • 40. Immunology of Human Cardiac Stem/Progenitor Cells for cardiac repairAllogenic Human Cardiac Progenitor Cells Low immune risk even within inflammatory environment Reparatory by promoting Treg and by their expression of PD-L1 *Regulatory T cells are implicated in cardiac repair after Myocardial infarction Tang TT, et al. Cell Physiol Biochem. 2010; Dobaczewski M, et al. Am J Pathol. 2010; Tang TT, et al. Basic Res Cardiol. 2012 *Myocardial PD-L1/PD1 control immune-mediated cardiac injury and polymorphonuclear inflammation Grabie N, et al. Circulation. 2007;116:2062 PD-L1-Dependent Allogenic-Driven Benefit Promotes Clinical Translation Highlights PD-L1 marker NK cells response Identify & Select Reactivity with anti-HLA antibodies Low-Risk/High-Benefit allogenic cardiac repair cells
  • 41. hCSCs-triggered Allogenic ResponseCD4+ T cells
  • 42. hCSCs immune-modulation of an ongoing T cell response PHA CSCs + alone Allo PBMC CSCs IFNγ MSCsT cell proliferation 89.1% 95.3% 71.6% 70.4% 28.1% CD4 90.7% 97.1% 69.6% 71.6% 19.6% CD8 CFSE
  • 43. CSCs can be recognized by anti HLA allo-antibodiesCSCsPBMC
  • 44. SUMMARYSUMMARY  CSCs express MHC I and MHC II under physiological & inflammatory situation  They display higher ALLOGENICITY than MSCs and are less powerful in down regulating an ongoing immune response  CSC capacity to induce or modulate an immune response is variable depending on both donor and recipient  CSCs are recognized by allo-anti-HLA sera, which can lead to in their elimination but could also be part of their paracrine effect Circulation Research 2012(in press)
  • 45. Immunosuppressive Therapy Mitigates Immunological Rejection of Human Embryonic Stem Cell Xenografts R.J SWIJNENBURG, S. SCHREPFER, J.A. GOVAERT, F. CAO, K. RANSOHOFF, A.Y SHEIKH, M. HADDAD, A.J CONNOLLY, M.M DAVIS, R.C ROBBINS, J.C WU PNAS, 2008,105:12991 IN VIVO VISUALIZATION OF HESC SURVIVALImmune Cell Stem Cell
  • 46. hCPC induced T Cell Response Allogeneic co culture: CFSE Labelled PBMC/ Mitomycin-C treated hCPC Allogeneic co culture: CFSE Labelled PBMC/ Mitomycin-C treated hCPC Low IFNγ & IL-2 productionLow response similar to MSC induced High IL10 Production hCPC induce low allogeneic T-cell response hCPC induce low allogeneic T-cell response
  • 47. 2012 Human cardiac Stem Cells characterization Cells from three different CH1, CH3, CH4 donors Endomyocardic Biopsy c-kit (48) CD90 (2880) SSEA-1 (269) Collagenase treatement C-kit purification/enrichment γ Cell counts IFN Cs SC M C- C PB CS M CS SSEA-4 CD166 CD44 (1779) (100) (14955) Oct4 Sox2 Nanog Fluorescence intensity β-actin DAPI DAPI DAPI NKx2.5 oct4 SSEA- 4 Cardiomyocyte DAPI DAPI DAPI FITC- PE-IgG FITC-IgG Cardiac differenciation Endothelial IgG potency Smooth muscle (In vitro)Nadal-Ginard B et al. Resident human cardiac stem cells: role in cardiac cellular homeostasisand potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med 2006;3
  • 48. Immunology of Human Cardiac Stem/Progenitor Cells for cardiac repair HLA-DR+ PD1+ Regulatory T cellshCPC in allogenic settings have the ability to induce tolerance, by promoting allo-stimulation and a contact and PD-L1-dependent regulatory response Lauden L. et al, Circ Res, 2013
  • 49. IN THE NEWS 2011• INDUCED PLURIPOTENT STEM CELLS(iPS) ARE IMMUNOGENIC & RESULT IN AUTO-IMMUNITY
  • 50. Immunogenicity of induced pluripotent stem cells T. Zhao, Z-N Zhang, Z. Rong and Y. Xu Nature, 2011, doi:10.1038/nature10135 * Proof of Principle Teratomal Immune Rejection/Tumor Regression ESCs from C57BL/6 B6 (IR/TR) 0 ESCs from 129/SvJ B6 +++ * Reprogramming of of B6 Embryonic Fibroblast (MEF) Oct4,Sox2,Klf4/Oct4,Sox2,Myc, Klf4 Retroviral Approach Episomal Approach ViPSCs EiPSCs IR/TR +++ B6 mice ++Immune Cell CD4 T cell infiltration/Cell necrosis Stem Cell
  • 51. Mechanisms?? * Gene profiling of EiPSCs Major findings * episomal vector is deleted * abnormal overexpression of endogenous genes - Hormad 1 (tumor specific Ag) - Spt1 (tumor specific Ag) - Zg16 * Immune Rejection/Tumor Rejection Major findings * CD4 CD8 mediated immune rejection through Ag specific (Zg16, Hormad1) T cells - confirmed by in vivo purified T cells (Ag specific) detected by (IFNγ release assay) upon co-culture with Ag-transfected DC from B6 mice Conclusion Break of Peripheral Tolerance/Expression of Minor AntigensImmune Cell Stem Cell
  • 52. Clinical translation can only be successful if good knowledge ofbiological processes linked to the therapeutic effect exists Cancer Stem Cells Stem Cells Pluripotency Self-renewal Plasticity Immune-modulation Factors promoting their Immune Behavior Common Distinct (PD-L1?, MHC II?) How these cells are Tolerated to persist Biomarkers Immune protocols Targets Eliminate Engraftment Combat Repair
  • 53. hCPC Immunomodulatory property PHA polyclonal stimulation PHA polyclonal stimulationhCPC are capable to modulate an ongoing Immune responsehCPC are capable to modulate an ongoing Immune response
  • 54. the function of MHC II molecules is not limited to their role as antigen-presentingstructures; they are receptors that by triggering a variety of signaling pathways canregulate cells activities from proliferation and maturation to apoptosis Could a signal via MHC II or I contribute to the Regenerative PARACRINE effect of allogenic CSCs???
  • 55. SUMMARYSUMMARY  CSCs express MHC I and MHC II under physiological & inflammatory situation  They display higher ALLOGENICITY than MSCs and are less powerful in down regulating an ongoing immune response  CSC capacity to induce or modulate an immune response is variable depending on both donor and recipient  CSCs are recognized by allo-anti-HLA sera, which can lead to in their elimination but could also be part of their paracrine effect Circulation Research 2012(in press)
  • 56. Additional Challenges• Injured myocardium is inflammatory:Immune reactivity increase• Presence of APC within the differenciated cell population(Endothelial ,Dentritic cells …)• MHC class I expression :NK cells susceptibility vs Cytotoxic T lymphocytes