The Role of Non-Classical Regulatory T Cells in HIV-1 Infection

Abstract

Regulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. While effects of classical \(CD25^{hi}FoxP3^+CD4^+\) regulatory T cells during HIV-1 infection have been analyzed in a series of recent investigations, very little is known about the role of non-classical regulatory T cells that do not express intracellular FoxP3. Here I evaluated two groups of non-classical Treg cells. One is phenotypically identified by the surface expression of HLA-G, an HLA class Ib molecule. The other Treg cell population is characterized by the surface expression of latency-associated peptide (LAP), a membrane-bound form of \(TGF-\beta\). Both HLA-G and LAP-expressing T cells are present in small proportions in peripheral blood of healthy individuals. I performed a systematic study on the phenotypic and functional profile of HLAG- and LAP- expressing regulatory T (Treg) cells in patients with different stages of HIV-1 infection. I found that HLA-G-expressing Treg cells were highly susceptible to HIV-1 infection, and were significantly reduced in individuals with progressive HIV-1 disease courses. Moreover, the proportion of \(HLA-G^+\) CD4 and CD8 T cells was positively correlated with CD4 T cell count and inversely correlated with markers of HIV-1 associated immune activation. Mechanistically, this correlation corresponded to a substantially increased ability of \(HLA-G^+\) Treg cells to inhibit bystander immune activation, while only minimally affecting functional properties of HIV-1-specific T cells. In contrast, no significant change in \(LAP^+\) Treg cell frequencies was found in progressive HIV-1 infection, and these frequencies were not correlated with immune activation. This observation was consistent with functional analysis, which indicated that \(LAP^+\) Treg cells did not suppress bystander activation. These investigations indicate an important role of \(HLA-G^+\) Treg cells for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection, and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression. In the meantime, \(LAP^+\) Treg cells do not appear to play an important role in determining HIV-1 disease outcome.