Background: The numeric homeostasis of T-cells is maintained by virtue of a balance between thymic differentiation (TD), antigen-driven proliferation (ADP), and homeostasis-driven proliferation (HDP). We hypothesize that perturbations of HDP may be involved in the pathogenesis of AIDS in HIV-infected humans and SIV-infected rhesus macaques (RM), and that in non-pathogenic SIV-infection of natural hosts (e.g., sooty mangabeys, SM) the preservation of HDP is instrumental in maintaining near normal CD4⁺ T-cell counts despite high levels of viral replication.

Methods: To investigate the features of HDP in primates, we have performed a comparative immunophenotypical analysis of proliferating (e.g., Ki67⁺) T-lymphocytes in the peripheral blood (PB), bone marrow (BM), and lymph nodes (LN) of 10 SIV-uninfected RM, 10 SIV-uninfected SM, and 10 SIV-infected SM. In addition, HDP was studied after CD8⁺ T-cell depletion as induced by OKT8F antibody in 4 SIV-infected and 2 SIV-uninfected SM. Plasma levels of IL-7 and IL-15, 2 cytokines involved in maintaining T-cell homeostasis, were measured by ELISA.

Results: We found that in SIV-uninfected primates the rates of CD4⁺ and CD8⁺ T-cell proliferation are significantly higher in the BM as compared to PB and LN, and that BM-derived Ki67⁺ T-cell appear to be enriched in a naïve-like T-cell subset showing a peculiarly “intermediate” level of CD62L expression. We thus hypothesized that BM is a preferential anatomic site for HDP of T-cells in primates, and we provide 3 sets of evidences to support this hypothesis. First, we found that BM, but not LN, is a site of increased CD4⁺ T-cell (but not CD8⁺ T-cell) proliferation in naturally SIV-infected SM, suggesting that this proliferation may in part represent HDP aimed at replacing the cells killed by virus infection. Second, we found a brisk increase in proliferating CD8⁺ T-cells in the BM of SMs in the first weeks after CD8⁺ T-cell depletion. Third, we found that the plasma level of IL-7 correlates significantly with the rates of proliferating T-cells in BM, both for CD4⁺ T-cells in SIV-infected SMs, and for CD8⁺ T-cells after CD8 depletion.

Conclusion: Our results suggest that 1) BM may be a preferential site for homeostatic proliferation of mature T-cells in primates; 2) this proliferation may be able to sense and respond to lineage-specific depletion of CD4⁺ or CD8⁺ T-cell; and that 3) IL-7 may be involved in reconstituting T-cell homeostasis after T-cell depletion.