Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism

Abstract

We hypothesized that regulatory T cells (Tregs) could play a beneficial role during HIV infection by controlling HIV replication in conventional T cells (Tcons). Purified Tregs and Tcons from healthy donors were activated separately. Tcons were infected with the X4 or R5 HIV strains and cultured with or without autologous Tregs. Coculture of Tcons and Tregs resulted in a dose-dependent inhibition of Tcon infection, which was significant when a 1:1 Treg:Tcon ratio was used. Treg suppression of HIV infection was largely mediated by contact-dependent mechanisms. Blockage of cytotoxic T-lymphocyte–associated antigen-4 did not significantly reduce Treg function. In contrast, Tregs acted through cAMP-dependent mechanisms, because the decrease of cAMP levels in Tregs, the blockade of gap junction formation between Tregs and Tcons, the blockage of CD39 activity, and the blockage of protein kinase A in Tcons all abolished Treg-mediated suppression of HIV replication. Our data suggest a complex role for Tregs during HIV infection. Although Tregs inhibit specific immune responses, their inhibition of HIV replication in Tcons may play a beneficial role, particularly during early HIV infection, when the effector immune cells are not yet activated. Such a protective role of Tregs could have a profound impact on infection outcome.

CD4+T Cells Develop Antiretroviral Cytotoxic Activity in the Absence of Regulatory T Cells and CD8+T Cells

“…In fact, cytotoxic activity of CD4 ϩ T cells against human pathogens has been described mainly for chronic viral infections (36 ϩ T cells have been described (48). In HIV infection, a cyclic AMP (cAMP)-dependent mechanism involving the enzyme CD39 was recently described (49). This effect requires cell-to-cell contact, which is in line with data from in vitro Treg suppression assays in the FV model (50).…”

Increased Frequency of Regulatory T Cells Accompanies Increased Immune Activation in Rectal Mucosae of HIV-Positive Noncontrollers

“…Furthermore, Favre et al recently postulated that in gut-associated lymphoid tissue (GALT), expansion of Treg in response to inflammation may support disease progression by preventing the recovery of Th17 cells, resulting in persistent mucosal barrier dysfunction and failure to clear translocated microbial products (31). However, other reports have suggested that Treg play a largely beneficial role, either by suppressing HIV-replication in conventional CD4 ϩ cells (66) or by limiting nonspecific immune activation (17,51). Indeed, because immune activation closely correlates with disease progression (19,40,63,88), it is possible that in the context of chronic infection the beneficial aspects of the Treg response outweigh the disadvantages.…”

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

“…In vitro, Tregs were shown to directly control HIV infection in susceptible targets, such as macrophages infected by a pseudotyped HIV (51) or infected conventional T cells (58), thus providing a potential mechanism for the correlative studies described above. In particular, we showed that cAMP was critical for this antiviral effect, acting either by direct transfer of cAMP through gap junctions or by the extracellular pathway, which involves CD39 activity (58).…”