Imbalanced Production of Cytokines by T Cells Associates with the Activation/Exhaustion Status of Memory T Cells in Chronic HIV Type 1 Infection

Abstract

Chronic HIV-1 infection is characterized by immune cell dysfunctions driven by chronic immune activation. Plasma HIV-1 viral load (VL) is closely correlated with disease progression and the level of immune activation. However, the mechanism by which the persistent presence of HIV-1 damages immune cells is still not fully understood. To evaluate how HIV-1 affects disruption of T cell-mediated immune responses during chronic HIV-1 infection we determined the functional profiles of T cells from subjects with chronic HIV-1 infection. We measured the capacity of peripheral blood mononuclear cells (PBMCs) to produce 25 specific cytokines in response to nonspecific T cell stimulation, and found that the capacity to produce Th-1-related cytokines (MIP-1α, MIP-1β, RANTES, IFN-γ, and MIG), sIL-2R, and IL-17, but not Th-2-related cytokines, was inversely correlated with plasma VL. The capacities to produce these cytokines were interrelated; notably, IL-17 production had a strong direct correlation with production of MIP-1α, MIP-1β, RANTES, and IFN-γ. In both CD4(+) and CD8(+) T cells, dysfunctional production of cytokines was associated with T cell activation (CD38 expression) and exhaustion (PD-1 and/or CTLA-4 expression) status of memory subsets. Although the capacity to produce these cytokines was recovered soon after multiple log(10) reduction of plasma viral levels by antiretroviral therapy, memory CD8(+) T cells remained activated and exhausted after prolonged virus suppression. Our data suggest that HIV-1 levels directly affect the ability of memory T cells to produce specifically Th1- and Th17-related cytokines during chronic HIV-1 infection.

Candida albicansStimulates IL-23 Release by Human Dendritic Cells and Downstream IL-17 Secretion by Vδ1 T Cells

“…In contrast, enhancement of these pathways may be beneficial for the treatment of C. albicans infection. The IL-23/IL-17 axis is also thought to contribute to immunity against HIV; therefore, stimulation of these pathways may also be of particular benefit to patients coinfected with HIV and C. albicans (38)(39)(40). HIV infects and kills IL-17-secreting CD4 + T cells, but Vd1 T cells are expanded in patients with HIV infection (25)(26)(27).…”

Distortion of memory Vδ2 γδ T cells contributes to immune dysfunction in chronic HIV infection

“…3,35 The imbalanced production of cytokines by T cells is associated with the activation and exhaustive status of memory T cells in HIV-infected patients. 36 Here, we assessed the production of IL-17 and IFN-c by cd T cells in HIV-infected (Figure 6a). We found that the frequency of IL-17-producing cd T cells was increased in the ACUTE and SP groups and significantly increased in the FP groups, compared with the healthy controls (Figure 6b).…”

Cytokine Diversity in the Th1-Dominated Human Anti-Influenza Response Caused by Variable Cytokine Expression by Th1 Cells, and a Minor Population of Uncommitted IL-2+IFNγ- Thpp Cells

“…This IFNγ+ bias is particularly clear in the response to long-circulating influenza strains, whereas a new pandemic influenza strain induced a mixed influenza-specific response [24] including both IL-2+IFNγ- and IL-2+IFNγ+ cells (abbreviated 2+γ- and 2+γ+, respectively). Similarly, the 2-γ+ cytokine expression pattern may be due to a population of exhausted Th1 cells [26]–[28] such as those expressing PD-1 and Tim3 [29], [30].…”