Akt and mTOR Pathways Differentially Regulate the Development of Natural and Inducible IL-17-Producing CD4+ T Cells
Authors: Kim Jiyeon S , Sklarz Tammarah , Waickman Adam , Li Ming O , Rathmell Jeffrey , Birnbaum Morris , Powell Jonathan , Jordan Martha S , Koretzky Gary A 
Published: October 2019

Abstract 838

Interleukin-17 (IL-17) producing CD4+ T helper (Th) cells, Th17 cells, are essential for immune responses against extracellular pathogens. Dysregulation of Th17 cells, meanwhile, leads to the pathogenesis of many inflammatory and autoimmune disorders, and the role of IL-17 and Th17 cells in cancer is the focus of extensive investigation. Recent studies have revealed that two distinct populations of Th17 cells exist. Inducible Th17 (iTh17) cells differentiate from naïve CD4+T cells in response to antigenic stimulation in the presence of an appropriate cytokine environment in the periphery, most notably the intestine, while natural Th17 (nTh17) cells acquire the capability of producing IL-17 during development in the thymus without a required differentiation step in the periphery. While iTh17 and nTh17 cells share many features, the signaling pathways essential for their development and function are not yet well understood. Using both genetic and pharmacological modulation of Akt activity, we show that Akt regulates the development of both nTh17 and iTh17 cells. Upon investigating the mechanism by which Akt controls the generation of both Th17 cell populations, we found that selective deficiency of mTORC1 activity did not affect nTh17 cells in contrast to the defective iTh17 cell generation in these mice (Rheb-deficient mice). The absence of mTORC2 activity, by deleting Rictor, an mTORC2-specific subunit, led to a severe defect in nTh17 cell development, while iTh17 cells were preserved in these mice. In line with the role of mTORC2 in nTh17 cells, mice deficient in both FoxO1 and FoxO3a, inhibitory proteins whose function is blocked by Akt and mTORC2, showed greatly enhanced nTh17 cell development. Mice receiving chronic rapamycin treatment, which has been demonstrated to inhibit not only mTORC1 but also mTORC2 activity, had greatly decreased nTh17 cells (Control: 29080±2426 nTh17s vs. Chronic Rapa: 1515±393.0 nTh17s, P=0.0004), while single dose of rapamycin, which interferes selectively with mTORC1 function, had no affect on these cells (Control: 29080±2426 nTh17s vs. Single Dose Rapa: 25310±2770 nTh17s, P=0.3631). In contrast, iTh17 cells were greatly diminished under both chronic and single dose of rapamycin treatment, supporting the distinct roles of mTORC1 and mTORC2 in controlling iTh17 versus nTh17 cell development. Finally, Akt isoform-specific activity also differentially contributes to nTh17 and iTh17 cell development. Selective deletion of Akt2, but not Akt1, resulted in defective iTh17 cell differentiation both in vitro and in vivo but preservation of nTh17 cells. Using mixed radiation bone marrow chimeras, we found that the aberrant iTh17 phenotype in Akt2-deficient mice is cell-intrinsic. Collectively, these data reveal novel mechanisms regulating nTh17 and iTh17 cell development and critical roles of Akt isoforms and the two distinct mTOR complexes in controlling the development of the Th17 cell subsets. Given the increasing interest in modulating Akt and mTOR pathways in various malignancies and the usage of mTOR inhibitors as immunosuppressants following tissue transplantation, our findings suggest that the effect on this aspect of immune system development should be taken into consideration when targeting these signaling pathways.

Disclosures:

No relevant conflicts of interest to declare.