Human TH17 Cells Are Long-Lived Effector Memory Cells

Human TH17 cells function as long-lived effector memory cells in the context of chronic disease. Forever Seventeen “It” is that quality possessed by some which draws all others with its magnetic force. Novelist Elinor Glyn In teen television drama parlance, T helper 17 (TH17) cells have been immunology’s “it girl” for the past few years. Discovered in 2007, this beguiling subset of TH cells is associated with autoimmune disease and long-term antitumor immunity, and the presence of these cells in tumors positively correlates with patient survival. Although mouse TH17 cells are believed to be short-lived, studies of advanced human cancers suggest that human TH17 cells persist, but little is known about the nature of these cells in the context of human disease. Now, Kryczek et al. define the detailed phenotype and functional aspects of human TH17 cells in diverse diseased human tissues and find that these cells resemble terminally differentiated, long-lived memory T cells with a twist. The authors used a well-defined human system to study the defining features and behavior of TH17 cells in the pathological microenvironments of human graft-versus-host disease, ulcerative colitis, and cancer. The fraction of TH17 cells was increased in these tissues during the chronic phases of the diseases. Furthermore, the TH17 cells not only displayed characteristics in common with terminally differentiated memory T cells, but also sported some genetic and functional signatures of their own. For example, disease-associated human TH17 cells wore the standard phenotypic markers of terminal differentiation and, in adoptive transfer experiments, drove persistent antitumor immunity. However, these versatile human T cells also displayed a high capacity for proliferative self-renewal, cell-type plasticity, and enriched expression of antiapoptotic genes. The cell membrane signaling protein Notch and the transcriptional regulatory protein hypoxia-inducible factor–1α (HIF-1α) were shown to jointly regulate the expression and function of the Bcl-2 family of antiapoptosis proteins. An intricate understanding of human TH17 cell biology in disease contexts should reveal new “it” molecules—therapeutic targets that permit TH17-directed treatment in patients with autoimmune diseases and advanced tumors. T helper 17 (TH17) cells have been shown to contribute to multiple disease systems. However, the functional phenotype and survival pattern of TH17 cells as well as the underlying mechanisms that control TH17 cells have been poorly investigated in humans, significantly hampering the clinical targeting of these cells. Here, we studied human TH17 cells in the pathological microenvironments of graft-versus-host disease, ulcerative colitis, and cancer; TH17 cell numbers were increased in the chronic phase of these diseases. Human TH17 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, TH17 cells mediated and promoted long-term antitumor immunity in in vivo adoptive transfer experiments. Furthermore, TH17 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 TH 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 TH17 cells. Together, these data indicate that human TH17 cells may be a long-lived proliferating effector memory T cell population with unique genetic and functional characteristics. Targeting TH17-associated signaling pathway would be therapeutically meaningful for treating patients with autoimmune disease and advanced tumor.