CCR4 and CCR6 Expression Characterizes Memory Tregs Subsets During HIV Infection and Correlates with Disease Progression

Abstract

Abstract Chemokine receptor expression on Tregs has been associated with pathogenesis of several diseases such as cancer, as CCR4 promotes Treg recruitment into tumors. During HIV infection, continuous Treg stimulation due to chronic inflammation has negative effects such as tissue fibrosis and limited antiviral response. We studied CCR4, CCR6, CXCR3 and CXCR5 on Treg subsets to identify homing patterns during HIV disease. CD4+ T cells (Tc) from 33 chronic untreated (CHR) and 52 antiretroviral treated (ART) HIV donors were characterized by FACS using memory markers. Tregs were defined as CD127lowCD25hi. Analysis was performed on Cytobank and Prism 6 using non-parametric tests. Tregs represented 7.0% and 8.0% of total CD4+ Tc in CHR and ART, respectively. Average Treg memory subsets distribution in CHR vs. ART was: Tscm=17.2% vs. 15.3%, Tcm=30.7% vs. 36.3% (p=0.0008), Ttm=27.4% vs. 25.7%. Chemokine receptor expression on total Tregs was (CHR vs. ART): R4=46.9% vs. 55.2% (p=0.0261), R6=31.6% vs. 40.1% (p=0.0043), X3=20.8% vs. 20.9% and X5=7.6% vs. 10.3%. In CHR, R4 (p=0.0007 r=0.3161) and R6 (p=0.0054 r=0.2241) frequencies correlated with CD4+ Tc count. Both markers were preferentially found on memory Treg (Tcm: R4=70.5%, R6=51.2%; Ttm: R4=93.4%, R6=65.7%) and had a significantly lower expression on non-Treg subsets (Tcm: R4=43.2%, R6=46.9%; Ttm: R4=37.0%, R6=29.9%). A similar pattern was also observed in people on ART. We showed that Tregs are characterized by R4 and R6 expression during treated and untreated HIV infection. Both molecules are markedly found on memory phenotypes, suggesting a role in controlling homing of effector Tregs. Accumulation of R4+R6+ Tregs may reflect a response to control chronic activation that persists after ART.