Primary and Chronic HIV Infection Differently Modulates Mucosal Vδ1 and Vδ2 T-Cells Differentiation Profile and Effector Functions

Abstract

Gut-associated immune system has been identified as a major battlefield during the early phases of HIV infection. γδ T-cells, deeply affected in number and function after HIV infection, are able to act as a first line of defence against invading pathogens by producing antiviral soluble factors and by killing infected cells. Despite the relevant role in mucosal immunity, few data are available on gut-associated γδ T-cells during HIV infection. Aim of this work was to evaluate how primary (P-HIV) and chronic (C-HIV) HIV infection affects differentiation profile and functionality of circulating and gut-associated Vδ1 and Vδ2 T-cells. In particular, circulating and mucosal cells were isolated from respectively whole blood and residual gut samples from HIV-infected subjects with primary and chronic infection and from healthy donors (HD). Differentiation profile and functionality were analyzed by multiparametric flow cytometry. P-HIV and C-HIV were characterized by an increase in the frequency of effector Vδ1-T cells both in circulating and mucosal compartments. Moreover, during P-HIV mucosal Vδ1 T-cells expressed high levels of CD107a, suggesting a good effector cytotoxic capability of these cells in the early phase of infection that was lost in C-HIV. P-HIV induced an increase in circulating effector Vδ2 T-cells in comparison to C-HIV and HD. Notably, P-HIV as well as HD were characterized by the ability of mucosal Vδ2 T-cells to spontaneously produce IFN-γ that was lost in C-HIV. Altogether, our data showed for the first time a functional capability of mucosal Vδ1 and Vδ2 T-cells during P-HIV that was lost in C-HIV, suggesting exhaustion mechanisms induced by persistent stimulation.

Mucosal and Systemic γδ+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection

“…Concomitantly, an increase in the Vδ1 CD8 + and CD4 + CD8 + subsets suggests the expansion of cytotoxic cells in response to infection. While we observed no depletion of Vδ2 T cells in SIV-infected macaques in comparison to the naïve animals, this population of cells has been reported to be lost and/or to become dysfunctional early following HIV/SIV infection (6-8, 16-18). Alteration in γδ T cells subsets has been widely shown during HIV infection (5, 17, 18, 44).…”

“…While we observed no depletion of Vδ2 T cells in SIV-infected macaques in comparison to the naïve animals, this population of cells has been reported to be lost and/or to become dysfunctional early following HIV/SIV infection (6-8, 16-18). Alteration in γδ T cells subsets has been widely shown during HIV infection (5, 17, 18, 44). In contrast only a single report concerning Vδ1/Vδ2 ratio alterations in SIV infected Rhesus macaques has appeared (8), showing a marginally significant difference in blood between naïve and SIV- infected macaques.…”

“…During HIV/SIV infection peripheral blood γδ T cell functions are dysregulated (6 - 8, 18). Therefore, the functionality of peripheral and mucosal Vδ1 and Vδ2 subsets from naïve and SIV-infected macaques was of interest.…”

“…Sex-related differences have been documented for various immunological parameters in mucosal tissues (41) as well as for their impact on AIDS disease progression (18, 35, 36). However, a potential sex bias in γδ T cell distribution and functionality has not been explored in HIV/SIV infection.…”

“…Disease progression is associated with depletion of Vδ2 T cells and expansion of Vδ1 T cells, leading to an inversion of the normal Vδ2/Vδ1 ratio in peripheral blood and mucosal tissues (6, 14-18). This alteration may result from infected cells accumulating phosphoantigens, leading to a brief period of activation and rapid expansion of Vδ2 T cells which subsequently decline and become dysfunctional by an unknown mechanism (18- 20). In contrast, microbial translocation across the gut epithelium may induce expansion of peripheral Vδ1 T cells (8).…”