The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

Abstract

The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.

Keywords: CCR6; HIV-1; Th17 cells; antiretroviral therapy; autoimmunity; cancer; gut.

Figure 1

The Th17 lineage heterogeneity during homeostasis and disease pathogenesis. This figure summarizes the heterogeneity of Th17 cells as discovered in mice and/or humans. (A) The concept of pathogenic versus non-pathogenic Th17 cells was originally established in the context of autoimmunity. Pathogenic Th17 cells are characterized by their ability to produce pro-inflammatory cytokines such as IL-17A, TNF-α, GM-CSF, and IFN-γ. These cells are identified as Th1Th17 or Th1* cells. They express on their surface the drug efflux pump MDR-1 and the receptor for IL-23, a cytokine found to promote pathogenic Th17 cell features. At the opposite, non-pathogenic Th17 cells are characterized by their ability to produce the immune-suppressive cytokine IL-10 or to express LAG-3; (B) the long-lived properties of certain Th17 subsets raised their potential contribution to cancer progression. However, the role of Th17 cells remains controversial and appears to vary from beneficial to deleterious depending on the type of cancer. Future studies are required to clarify these differences; (C,D) in humans, four subsets of CCR6+ Th17 cells were identified by our group based on their differential expression of CCR4 and CXCR3, as follows: CCR4+CXCR3− (Th17), CCR4−CXCR3+ (Th1 Th17 or Th1*), CCR4−CXCR3− (double negative, CCR6+DN), and CCR4+CXCR3+ (double positive, CCR6+DP). In HIV-uninfected individuals (C), Th17, Th1Th17, and CCR6+DN subsets are present in the blood at similar frequency, whereas CCR6+DP cells are less predominant. In chronically HIV-infected individuals receiving viral suppressive antiretroviral therapy (ART) (D), the frequency of Th17, Th1Th17, and CCR6+DP is dramatically decreased. However, the frequency of CCR6+DN cells is preserved in the blood and this subset is the most predominant in the lymph nodes of ART-treated individuals.