Background:  CD4⁺CD25⁺ regulatory T cells (Treg) have been demonstrated to inhibit antigen-specific CD4⁺ and CD8⁺ T-cell responses in the context of pathogenic infections in mice; an effect that can contribute to the persistence of infection. A virtually identical cellular population has been identified in humans. To date the effect of CD4⁺ CD25⁺ Treg cells in the context of HIV disease has not been investigated.

Methods:  PBMC subsets were isolated from HIV-infected donors (n=25; on or off anti-retroviral therapy) using immunomagnetic beads.  CD25⁺CD4⁺ (±CD45RA^–-) T cells were phenotyped (FACS/Western blot) and tested for their effects on HIV-specific proliferation (LPA or CFSE) and cytokine (secreted or intracellular (ICC)) production by CD25^–CD4⁺ or CD8⁺ T cells.  

Results: CD25⁺CD4⁺ T cells isolated from HIV-infected donors exhibited surface and nuclear (FoxP3 transcription factor) markers consistent with regulatory T cells.  A modest elevation in the frequency of the CD25^+hi CD4⁺ subset was seen in HIV-infected versus uninfected donor PBMC.  HIV p24-induced proliferation and cytokine (IL-2, IFN-g) production by memory CD4⁺ T cells were enhanced following depletion, and suppressed by re-addition, of CD25⁺ CD45RA-CD4⁺ T cells in a subset of donors (15/25); this effect was independent of TGF-b and IL-10. Depletion of CD25⁺ CD4⁺ T cells resulted in increased frequencies HIV Gag peptide-induced IFNg⁺ CD8⁺ T cells from most donors and increased spontaneous IFN-g production by CD8⁺ cells from donors with high viral loads. Furthermore, CD25+, but not CD25-, CD4+ T cells suppressed the ability of effector (perforin⁺) CD8⁺ T cells to proliferate in response to autologous HIV super-infected target cells.

Conclusions: These data demonstrate that a subset of CD25⁺CD4⁺ T cells isolated from HIV-infected donors exhibit a CD25⁺CD4⁺ Treg-like phenotype and suppress HIV-specific immune responses in vitro.  These findings suggest that CD25⁺CD4⁺ Treg-mediated immunosuppression may restrict the ability of both CD4⁺ and CD8⁺ T cells to effectively control HIV replication in vivo.

Keywords: CD25+CD4+ Treg; HIV-specific; immune response