Regulatory T cells in HIV infection: can immunotherapy regulate the regulator?

Abstract

Regulatory T cells (Tregs) have a dominant role in self-tolerance and control of autoimmune diseases. These cells also play a pivotal role in chronic viral infections and cancer by limiting immune activation and specific immune response. The role of Tregs in HIV pathogenesis remains poorly understood as their function, changes according to the phases of infection. Tregs can suppress anti-HIV specific responses and conversely can have a beneficial role by reducing the deleterious impact of immune activation. We review the frequency, function and homing potential of Tregs in the blood and lymphoid tissues as well as their interaction with dendritic cells in the context of HIV infection. We also examine the new insights generated by recombinant IL-2 and IL-7 clinical trials in HIV-infected adults, including the immunomodulatory effects of Tregs. Based on their detrimental role in limiting anti-HIV responses, we propose Tregs as potential targets for immunotherapeutic strategies aimed at decreasing Tregs frequency and/or immunosuppressive function. However, such approaches require a better understanding of the time upon infection when interfering with Treg function may not cause a deleterious state of hyperimmune activation.

Figure 1

The Treg regulatory pathways. (a) The ability of Tregs to induce immune suppression is mediated via (1) inhibitory cytokines; (2) induction of apoptosis by granzyme/perforin pathway; (3) CD39/CD73/adenosine pathway; (4) direct transfer of cAMP via GAP junction; (5) inhibition of DC function by CD80/CD86 and CTLA-4 interaction; and (6) the catabolism of tryptophan via IDO enzyme. (b) Dual function of HIF-1α in regulation of Treg and Th17 cells.

Figure 2

The impact of cytokine-based immunotherapy on Treg in HIV infection. The IL-2 immunotherapy results predominantly in the expansion of Treg, which express high levels of the IL-2 receptor chain CD25. In contrast, IL-7 immunotherapy may preferentially favour the effector T cell population without inducing Tregs because Tregs express low levels of the IL-7 receptor chain CD127.