RESUMO
The present investigation explored age-related alterations in T cell populations mediating allospecific responses in vivo. Healthy aged and young H-2b and H-2bxH-2k mice were engrafted with major histocompatibility complex (MHC) class II-disparate bm12 skin, rejection of which requires CD8+ T cells, and MHC class I-disparate bm1 skin, rejection of which requires CD8+ T cells. Aged mice of both genders exhibited prolonged survival of bm12 skin grafts relative to their young counterparts but rejected bm1 skin grafts at a rate equivalent to that of young mice. Consistent with prolonged survival of bm12 skin grafts, markedly diminished levels of Iabm12 CTL activity were elicited from T cells of aged mice in vitro. However, no such decline was observed in the level of Kbm1 CTL from T cells of aged mice. The alterations in Iabm12 allospecific responses were not attributable to quantitative changes in CD4+ T cells of aged mice, and addition of soluble T cell helper factors to response cultures of aged mice did not augment Iabm12 cytotoxic T lymphocytes activity. These data demonstrate that aging fundamentally affects CD4+ T cell-mediated allospecific responses particularly in vivo, and that deficient generation of soluble T cell helper factors alone cannot explain this deficit.
Assuntos
Envelhecimento/imunologia , Rejeição de Enxerto/imunologia , Transplante de Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Anticorpos Monoclonais , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/fisiologia , Testes Imunológicos de Citotoxicidade , Feminino , Interleucina-2/fisiologia , Isoantígenos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Baço/citologiaRESUMO
The present study was undertaken to define the cellular mechanisms involved in the rejection of major histocompatibility complex (MHC) class I disparate skin grafts by mice depleted of CD8+ T cells in vivo. Mice were effectively depleted of CD8+ T cells by adult thymectomy followed by in vivo administration of anti-CD8 monoclonal antibody (mAb) and then engrafted with allogeneic skin. We found that CD8 depleted mice did reject MHC class I disparate skin grafts, but only when the grafts also expressed additional alloantigens. Despite the marked depletion of CD8+ T cells in these mice, we found that their rejection of MHC class I disparate grafts was mediated by CD8+ cytolytic T lymphocyte (CTL) effectors that had escaped depletion. These CD8+ CTL effectors were unique in that: (a) their generation was dependent upon the injected anti-CD8 mAb and upon exposure to class I MHC alloantigens expressed on the engrafted skin, and (b) their effector function was resistant to blockade by anti-CD8 mAb. We observed that the additional alloantigens coexpressed on MHC class I disparate grafts that triggered graft rejection in CD8-depleted mice could be MHC-linked or not and that they functioned in these rejection responses to activate third party specific CD4+ T helper (Th) cells to provide helper signals for the generation of CD8+ anti-CD8 resistant CTL effector cells. Thus, mice depleted of CD8+ T cells by thymectomy and in vivo administration of anti-CD8 mAb harbor a unique population of anti-CD8 resistant, CD8+ effector cells that mediate anti-MHC class I responses in vivo and in vitro, but require help from third party specific Th cells to do so.
Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos H-2/imunologia , Transplante de Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8 , Rejeição de Enxerto , Imunidade Celular , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos , Linfócitos T Auxiliares-Indutores/imunologiaAssuntos
Rejeição de Enxerto , Síndrome de Imunodeficiência Adquirida Murina/imunologia , Transplante de Pele/imunologia , Animais , Teste de Histocompatibilidade , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/microbiologia , Retroviridae/patogenicidade , Linfócitos T/imunologia , Transplante HomólogoRESUMO
In vivo rejection of MHC class II disparate skin allografts has been thought to involve IFN-gamma-induced expression of MHC class II alloantigens because less than 3% of skin epidermal cells express MHC class II alloantigens constitutively. In our study we directly tested this hypothesis by examining the effect of in vivo administered anti-IFN-gamma mAb on rejection of MHC class II disparate skin allografts, and comparing its effect on rejection of MHC class I disparate skin allografts placed on the same individual mice. We found that anti-IFN-gamma mAb blocked the rejection of MHC class II disparate skin allografts, but had no effect on the rejection of MHC class I disparate skin allografts. These results demonstrate that endogenously produced IFN-gamma is critical for rejection of MHC class II disparate skin allografts, but not for rejection of MHC class I disparate skin allografts. Thus, this study strongly supports the concept that MHC class II rejection responses require IFN-gamma induced MHC class II expression on keratinocytes of the allograft.