Abstract
CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.
Highlights
CD161 is a member of the C-type lectin family, and was originally described as a natural killer (NK) cell receptor; it was subsequently found expressed on subsets of both CD4+ and CD8+ T cells [1].CD161 ligation on T cells can provide a co-stimulatory signal for T cell receptor (TCR)-mediated activation [2]
As CD161+ CD4+ T cells are memory cells, expressing high levels of CCR5, CCR6, and integrin α4, a phenotype associated with susceptibility to HIV-1 infection, we studied how these cells are affected during untreated acute HIV-1 infection (AHI)
The capacity of CD161+ CD4+ T cells to produce IFNγ, tumor necrosis factor (TNF), and IL-17 was decreased post-HIV-1 infection compared to pre-infection (Figure 4). These results suggest that the CD161+ CD4+ T cell population is significantly altered during untreated AHI
Summary
CD161 is a member of the C-type lectin family, and was originally described as a natural killer (NK) cell receptor; it was subsequently found expressed on subsets of both CD4+ and CD8+ T cells [1].CD161 ligation on T cells can provide a co-stimulatory signal for T cell receptor (TCR)-mediated activation [2]. CD161 is a member of the C-type lectin family, and was originally described as a natural killer (NK) cell receptor; it was subsequently found expressed on subsets of both CD4+ and CD8+ T cells [1]. Several studies have shown that CD161 expression on T cells is associated with the capacity to produce interleukin (IL)-17 [3,4,5]. Innate-like T cells, such as mucosal associated invariant T (MAIT) [6] and invariant natural killer T (iNKT) [7] cells, are all characterized by CD161 expression. Conventional CD8+ and CD4+ T cells expressing CD161 were reported to share a transcriptional program with innate-like T cells, as well as responsiveness to cytokine stimulation [8]. CD161 expression on CD4+ T cells is associated with markers of gut homing receptors, such as C-C chemokine receptor (CCR) 6 and integrin α4β7 [5]
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