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

J Infect Dis. 2019 Jul 31;220(5):830-840. doi: 10.1093/infdis/jiz123.


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.

Keywords: CCL20; CCL25; CD8; CXCR3; HIV-1; IFN-γ; IL-18; Th1; gut.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Retroviral Agents / therapeutic use
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Movement
  • Chemokine CCL20 / metabolism
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL11 / metabolism
  • Chemokine CXCL9
  • Chemokines, CC / metabolism
  • Cytokines / metabolism
  • HIV Infections / metabolism*
  • HIV Infections / therapy
  • Humans
  • Interferon-gamma / metabolism*
  • Interleukin-18 / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestine, Small / metabolism*
  • Receptors, CXCR3 / metabolism*
  • Th1 Cells / metabolism
  • Th17 Cells / metabolism*


  • Anti-Retroviral Agents
  • CCL20 protein, human
  • CCL25 protein, human
  • CXCL10 protein, human
  • CXCL11 protein, human
  • CXCL9 protein, human
  • CXCR3 protein, human
  • Chemokine CCL20
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CC
  • Cytokines
  • IL18 protein, human
  • Interleukin-18
  • Receptors, CXCR3
  • Interferon-gamma