Homeostasis and function of regulatory T cells in HIV/SIV infection

Abstract

Regulatory T cells (Tregs) play a pivotal role in the maintenance of tolerance as well as in the control of immune activation, particularly during chronic infections. In the setting of HIV infection, the majority of studies have reported an increase in Treg frequency but a decrease in absolute number in all immune compartments of HIV-infected individuals. Several nonexclusive mechanisms have been postulated to explain this preferential Treg accumulation, including peripheral survival, increased proliferation, increased peripheral conversion, and tissue redistribution. The role played by Tregs during HIV infection is still poorly understood, as two opposing hypotheses have been proposed. A detrimental role of Tregs during HIV infection was suggested based on the evidence that Tregs suppress virus-specific immune responses. Conversely, Tregs could be beneficial by limiting immune activation, thus controlling the availability of HIV targets as well as preventing immune-based pathologies. Despite the technical difficulties, getting a better understanding of the mechanisms regulating Treg dynamics remains important, as it will help determine whether we can successfully manipulate Treg function or number to the advantage of the infected host. The aim of this review is thus to discuss the recent findings on Treg homeostasis and function in the setting of HIV infection.

Fig 1

Potential mechanisms that may explain selective accumulation of Tregs during HIV infection. Treg accumulation could be due to different, as well as synergistic, mechanisms. (1) Preferential survival. HIV infects both Tregs and conventional CD4⁺ T cells (Tcon), but Tregs could be less susceptible to cell death than Tconvs. (2) Increased proliferation. HIV could increase the expansion of Tregs by inducing these cells to enter into the cell cycle. (3) Tissue redistribution. HIV infection could induce upregulation of molecules, such as CD62L and integrin-α4β7, that are involved in T cell chemotaxis, leading the migration of Tregs from the blood to the lymphoid tissues, where these cells accumulate. (4) Peripheral conversion. Interaction of HIV-exposed DCs with non-Tregs could lead to conversion into induced Tregs (iTreg).

Fig 2

Potential role of Tregs during HIV infection. (A) Increased Treg frequency during HIV infection can lead directly to decreased T cell activation, thus decreasing the availability of target cells for HIV replication. Tregs can also decrease the capacity of DCs to transmit the virus to CD4⁺ T cells as well as decrease viral replication in macrophages. Importantly, Tregs can decrease viral replication by directly affecting the HIV replication cycle. On the other hand, Tregs can decrease CD4 and CD8 HIV-specific responses either directly or indirectly by decreasing the maturation of DCs, thus impairing DC capacity to induce immune responses. Tregs also contribute to immune dysfunction by secreting large amounts of TGF-β, thus contributing to lymphoid tissue fibrosis. (B) Based on the literature, a potential model for Tregs' role is that they may have an overall beneficial effect during early acute HIV infection, before HIV-specific immune responses are fully activated, by controlling T cell activation and decreasing the availability of target cells for HIV replication and transmission. In contrast, during the late acute and chronic phases, increased Treg frequency may have an overall-negative role, as the Treg suppressive effect on HIV antiviral immune responses predominates.