Little is known about the mechanisms regulating T cell homeostasis in primates. The overall aim of this project is to study the homeostatic regulation of T cells in healthy rhesus macaques (RM) and sooty mangabeys (SM) via antibody-induced depletion of specific T cell subsets. We believe that this proposal is relevant to AIDS research due to the specific features of SIV-infection in the two species, i.e. pathogenic in RM and non-pathogenic in SM. If our study identifies differences in T cell homeostasis between RM and SM, we may then hypothesize that these differences play a role in determining the clinical outcome after SIV-infection. In earlier studies we showed that although CD4+ T cells are lost due to the cytopathic effect of the virus during both pathogenic and non-pathogenic infections, only in pathogenic infections is the homeostasis of T cells lost. This observation suggests that the failure of T cell homeostasis may play a role in the pathogenesis of AIDS, and that treatments aimed at reconstituting this homeostasis may be used in the clinical management of HIV-infected patients. Here we propose to study the lymphocyte repopulation that follows CD4+ and CD8+ T cell depletion by sequentially sampling bone marrow (BM), peripheral blood (PB) and lymph nodes (LN). The performed analyses will include: (1) immunophenotypic studies, (2) determination of levels of recent thymic emigrants, and (3) examination of levels of cytokines, i.e. IL-7, IL-15and IL-2, that may play a role in T cell homeostasis. In this application we also propose to evaluate the role of the thymus in T cell homeostasis by performing CD4+ and CD8+ T cell depletions in both normal and thymectomized animals. We believe that this comparative study may provide information on (1) the differential role of BM, LN and thymus in T cell homeostasis; (2) the specific features of the homeostasis ofCD4+ and CD8+ T cells; (3) the immunophenotype of T cells that are proliferating via homeostatic mechanisms; and (4) the role of cytokines in reconstituting acutely depleted T cell populations. Importantly, this approach may allow us to define differences in the way T cell homeostasis is maintained in RM vs SM, which could provide clue regarding the markedly different impact of SIV-infection in the two species. In all, we believe that this project may provide useful information on the homeostasis of T cells in primates, and how the failure of this homeostasis may play a role in the pathogenesis of AIDS.
| Zeng, Ming; Paiardini, Mirko; Engram, Jessica C et al. (2012) Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood 120:1856-67 |
| Engram, Jessica C; Cervasi, Barbara; Borghans, Jose A M et al. (2010) Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates. Blood 116:748-58 |
| Paiardini, Mirko; Cervasi, Barbara; Engram, Jessica C et al. (2009) Bone marrow-based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis. Blood 113:612-21 |
| Pandrea, Ivona; Silvestri, Guido; Onanga, Richard et al. (2006) Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: common patterns and species-specific differences. J Med Primatol 35:194-201 |
| Hurtrel, B; Petit, F; Arnoult, D et al. (2005) Apoptosis in SIV infection. Cell Death Differ 12 Suppl 1:979-90 |
