Human TH17 Cells Are Long-Lived Effector Memory Cells

T helper 17 (T(H)17) cells have been shown to contribute to multiple disease systems. However, the functional phenotype and survival pattern of T(H)17 cells as well as the underlying mechanisms that control T(H)17 cells have been poorly investigated in humans, significantly hampering the clinical targeting of these cells. Here, we studied human T(H)17 cells in the pathological microenvironments of graft-versus-host disease, ulcerative colitis, and cancer; T(H)17 cell numbers were increased in the chronic phase of these diseases. Human T(H)17 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(H)17 cells mediated and promoted long-term antitumor immunity in in vivo adoptive transfer experiments. Furthermore, T(H)17 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-1 alpha and Notch collaboratively controlled key antiapoptosis Bcl-2 family gene expression and function in T(H)17 cells. Together, these data indicate that human T(H)17 cells may be a long-lived proliferating effector memory T cell population with unique genetic and functional characteristics. Targeting T(H)17-associated signaling pathway would be therapeutically meaningful for treating patients with autoimmune disease and advanced tumor.