Potential Role of Vδ2+ γδ T Cells in Regulation of Immune Activation in Primary HIV Infection

Abstract

Although conventional regulatory T cells (Tregs) are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI). Our previous data suggested that double negative (DN) T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI). In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT), we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+) γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro-inflammatory cytokine profile and participate in sustenance of immune activation.

γδ T‐cell responses during HIV infection and antiretroviral therapy

“…50 Given early reports that Vd2 T cells lacked expression of CD4 51 and were resistant to direct HIV infection, 52 there has been a strong emphasis on determining the mechanism of peripheral depletion, albeit with little consensus. 32,33 Vd2 depletion is also associated with a reduction of antigen-induced IFNc 46 /TNFa 57 /TGFb 47 production and proliferative/cytotoxic capacity 48,58,59 in the residual Vd2 population. 53 gp120-induced cross-linking of CCR5 and a4b7 on CD4 À Vd2 T cells results in the activation of the p38 caspase pathway and eventual apoptosis, without productive infection of the cell.…”

“…Li and Pauza presented evidence implicating the HIV gp120 binding proteins a4b7 and CCR5 in mediating Vd2 depletion in viremic patients. 32,33,47 Although all Vd2 memory subsets exhibit significant increases in activation during acute and chronic HIV infection, 33,47 T EMRA cells tend to exhibit the highest levels of activation as measured by CD38 expression. To date, this mechanism remains to be confirmed, but analysis of existing data from preclinical studies of a4b7 monoclonal antibody (mAb) blockade 54-56 may provide interesting insights into this phenomenon.…”

“…Several studies have confirmed that the relative enrichment of Vd1 cells as a proportion of the total cd T-cell population is also reflected as an increase in absolute Vd1 33,[38][39][40][41][42][43][44][45][46][47] ) T-cell count in the periphery. 37,40,47 In acute, chronic and naturally controlled infection, the majority of Vd1 cells exhibit a T EMRA phenotype, 37,40,41,44 which correlates with absolute Vd1 T-cell counts 47 and is suggestive of antigen-driven proliferation and activation. 37,40,47 In acute, chronic and naturally controlled infection, the majority of Vd1 cells exhibit a T EMRA phenotype, 37,40,41,44 which correlates with absolute Vd1 T-cell counts 47 and is suggestive of antigen-driven proliferation and activation.…”

“…Both cross-sectional and longitudinal cohort studies find that ART fails to restore normal frequencies or numbers of Vd2 T cells. 47 Data on memory subset distribution is more controversial, with some evidence that the expanded TEMRA population persists during ART, 71,73 while other studies show a reduction in TEMRA frequencies that closely resemble uninfected controls. 76 Phenotypically, more studies report residual activation of the Vd2 subset during ART compared with healthy controls 33,71 than normalisation of activation.…”

“…[11][12][13][14][15] HIV-1 (herein referred to as HIV) infection still remains one of the most challenging health issues worldwide. [31][32][33]35,38,[41][42][43][44][45][46][47][48] Subsequent investigations have focused on the mechanisms behind this expansion/depletion, as well as the relationship of cd T subsets to HIV disease progression. Despite increasing awareness of the disease and improved access to antiretroviral therapy (ART), approximately 5000 individuals become newly infected every day.…”