Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection

Abstract

The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.

Impact of Early ARV Initiation on Relative Proportions of Effector and Regulatory CD8 T Cell in Mesenteric Lymph Nodes and Peripheral Blood During Acute SIV Infection of Rhesus Macaques

“…In line with our findings, no differences in CCR6 + CD8 T-cell frequencies between SIV/HIV-infected and uninfected subjects have been reported ( 55 , 56 ). Similar to our data, increased frequencies of CXCR3 + CD8 T cells in both the blood and peripheral LNs have been reported during acute infection, which then decrease with disease progression ( 57 , 58 ). In addition, Wacleche et al proposed that CD8 T-cell recruitment to the GALT was mainly dependent upon integrin β7 and chemokine receptor CXCR3, while a limited CD4 and CD8 T-cell colocalization mediated by CCR6-dependent recruitment could contribute to poor viral control of the infection ( 59 ).…”

The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

“…Such findings are concordant with studies of HIVinfected individuals which have also reported reduced frequencies of Th22 cells in these compartments [189][190][191], and this has been associated with damage towards the mucosal barrier and increased microbial translocation [191]. Although virologic suppression by ART does not restore the frequency of Th17 cells in the gut due to perturbations in the CCR6-CCL20 chemotactic axis [182][183][184], Th22 cells by contrast are reconstituted [182]. These cells preferentially home towards the gut in a CCL20-dependent manner but can migrate via the CCR10-CCL28 chemotactic axis as an alternative when CCL20 levels are reduced as in ARTsuppressed HIV-infected individuals.…”

“…Importantly, sustained virologic suppression by ART does not restore the Th17 cell population in the gut in the majority of HIV-infected individuals [182]. Although these cells typically home towards the gut via the CCR6-CCL20 chemotactic axis, this is impaired in ART-suppressed, HIVinfected individuals as there is a decreased production of CCL20 by enterocytes in response to IFN-γ secretion by Th1 cells as well as IL-10 and TGF-β secretion by Tregs [183,184]. Recently, Th17 cells were found to be enriched in the inner foreskin of uninfected men compared to the outer foreskin [185].…”

Hepatitis E virus replication in human intestinal cells

“…Primary small intestine epithelial cells were isolated and maintained in culture as previously described 11 12. Briefly, human intestinal tissues were obtained from resections of small bowel during elective surgery at the Digestive Surgery Department, Toulouse University Hospital.…”

“…Primary intestinal cells were differentiated as previously described 11 12. Briefly, cells were cultured on Transwell inserts (0.33 cm² area, 0.4 µm pore size, polyester membrane; Corning) covered with Matrigel (Corning).…”