Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells.

Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6(+) T(M) cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.

Th17 cells and HIV infection.

PURPOSE OF REVIEW: This review summarizes the recent literature about the potential perturbation and role of Th17 cells in HIV pathogenesis. We discuss the recent findings on Th17 deficiency in HIV/simian immunodeficiency virus (SIV) infection and how this deficiency may impact the mucosal host defenses, potentially contributing to chronic immune activation. RECENT FINDINGS: Th17 cells have been implicated in host defense against a variety of pathogens and are involved in the pathogenesis of autoimmune diseases. Recently, Th17 cells were shown to be perturbed during HIV infection in humans and SIV infection in nonhuman primates. Th17 cells were found to be infected in vitro by HIV and SIV and are significantly depleted in the gastrointestinal tract of HIV-infected individuals. In monkeys, Th17 cells are only depleted in the pathogenic SIV infection of rhesus macaques, which correlates with the progression to AIDS in these primates, whereas they remain intact in the nonpathogenic SIV infection of African green monkeys or sooty mangabeys. SUMMARY: Th17 cells appear to be perturbed during HIV and SIV infection. This finding could have important implications in understanding the disruption of mucosal defenses in the gastrointestinal tract and potentially in predicting opportunistic infections during the course of HIV disease.