Human T H 17 Cells Are Long-Lived Effector Memory Cells

Abstract

T helper 17 (T_H17) cells have been shown to contribute to multiple disease systems. However, the functional phenotype and survival pattern of T_H17 cells as well as the underlying mechanisms that control T_H17 cells have been poorly investigated in humans, significantly hampering the clinical targeting of these cells. Here, we studied human T_H17 cells in the pathological microenvironments of graft-versus-host disease, ulcerative colitis, and cancer; T_H17 cell numbers were increased in the chronic phase of these diseases. Human T_H17 cells phenotypically resembled terminally differentiated memory T cells but were distinct from central memory, exhausted, and senescent T cells. Despite their phenotypic markers of terminal differentiation, T_H17 cells mediated and promoted long-term antitumor immunity in in vivo adoptive transfer experiments. Furthermore, T_H17 cells had a high capacity for proliferative self-renewal, potent persistence, and apoptotic resistance in vivo, as well as plasticity—converting into other types of T_H cells. These cells expressed a relatively specific gene signature including abundant antiapoptotic genes. We found that hypoxia-inducible factor–1α and Notch collaboratively controlled key antiapoptosis Bcl-2 family gene expression and function in T_H17 cells. Together, these data indicate that human T_H17 cells may be a long-lived proliferating effector memory T cell population with unique genetic and functional characteristics. Targeting T_H17-associated signaling pathway would be therapeutically meaningful for treating patients with autoimmune disease and advanced tumor.