Caecum OX40DCD4 T-cell subset associates with mucosal damage and key markers of disease in treated HIV-infection

Abstract

bstract Background: Blood OX40-expressing CD4 T-cells from antiretroviral (ART)-treated people living with HIV (PWH) were found to be enriched for clonally-expanded HIV sequences, hence contributing to the HIV reservoir. OX40-OX40L is also a checkpoint regulator of inflammation in multiple diseases. We explored gut mucosal OX40þCD4þ T-cells and their potential significance in HIV disease. Methods: Biopsies of caecum and terminal-ileum of ART-treated PWH (n Z 32) were obtained and mucosal damage and HIV reservoir were assessed. Mucosal OX40þ and Ki67þ CD4 T-cell subsets, as well as several tissue T-cell subsets modulating mucosal integrity and homeostasis (Th17, Th22, Treg, Tc17, Tc22, IL17þTCRgd, IL22þTCRgd) were quantified. Inflammatoryrelated markers, T-cell activation and thymic output were also determined in blood samples. Correlations were explored using Spearman rank test and corrected for multiple comparisons by Benjamini-Hochberg. Results: Compared to healthy controls, a high frequency of mucosal, mainly caecum, CD4 Tcells were OX40þ in PWH. Such frequency strongly correlated with nadir CD4 (r Z 0.836; p < 0.0001), CD4/CD8 ratio (r Z 0.630; p Z 0.002), caecum mucosal damage (r Z 0.606; p Z 0.008), caecum Th22 (r Z 0.635; p Z 0.002), caecum Th17 (r Z 0.474; p Z 0.03) and thymic output (r Z 0.686; p < 0.001). It also correlated with Neutrophil-toLymphocyte Ratio and blood CD4 T-cell activation and tended to with mucosal HIV reservoir. Conclusion: High frequencies of caecum OX40þCD4 T-cells are found in people with HIV (PWH) and successful viral control. Interestingly, this cellular subset reflects key markers of disease and peripheral T-cell activation, as well as HIV-driven mucosal damage. OX40þCD4 T-cells deserve further investigation since they could expand because of T-cell homeostatic proliferation and relate to the Th22/Th17 gut mucosal ratio.