The Inducible Costimulator (ICOS) Is Critical for the Development of Human T _H 17 Cells

Abstract

Human T helper 17 (TH17) cells regulate host defense, autoimmunity, and tumor immunity. Although cytokines that control human TH17 cell development have been identified, the costimulatory molecules important for TH17 cell generation are unknown. Here, we found that the inducible costimulator (ICOS) was critical for the differentiation and expansion of human TH17 cells. Human cord blood contained a subset of CD161+CD4+T cells that were recent emigrants from the thymus, expressed ICOS constitutively, and were imprinted as TH17 cells through ICOS signaling. ICOS stimulation induced c-MAF, RORC2, and T-bet expression in these cells, leading to increased secretion of interleukin-21 (IL-21), IL-17, and interferon-γ (IFN-γ) compared with cells stimulated with CD28. Conversely, CD28 ligation abrogated ICOS costimulation, dampening RORC2 expression while promoting the expression of the aryl hydrocarbon receptor, which led to reduced secretion of IL-17 and enhanced production of IL-22 compared with cells stimulated with ICOS. Moreover, ICOS promoted the robust expansion of IL-17+IFN-γ+ human T cells, and the antitumor activity of these cells after adoptive transfer into mice bearing large human tumors was superior to that of cells expanded with CD28. The therapeutic effectiveness of ICOS-expanded cells was associated with enhanced functionality and engraftment in vivo. These findings reveal a vital role for ICOS signaling in the generation and maintenance of human TH17 cells and suggest that components of this pathway could be therapeutically targeted to treat cancer or chronic infection and, conversely, that interruption of this pathway may have utility in multiple sclerosis and other autoimmune syndromes. These findings have provided the rationale for designing new clinical trials for tumor immunotherapy.

B7h Triggering Inhibits the Migration of Tumor Cell Lines

“…Moreover, we found that B7h triggering in human DCs increases the secretion of IL-23 (which is involved in Th17 expansion and survival) and supports Th17 cell activity (18). Finally, ICOS triggering in T cells (which is blocked by ICOS-Fc) is involved in the differentiation of both Tregs and Th17 cells (17,(31)(32)(33); however, its support of Treg differentiation prevails in the tumor environment (34,35).…”

Antibody-Opsonized Bacteria Evoke an Inflammatory Dendritic Cell Phenotype and Polyfunctional Th Cells by Cross-Talk between TLRs and FcRs

“…It is clear that onset of these infDCs resides in inflammatory microenvironments. However, the trigger for DCs to develop into this inflammatory phenotype remains unknown and was not dependent on ICOS/ICOS-L interaction, which is important for Th17 polarization (21,47 DCs]), we observed that iDCs activated with IgG-opsonized E. coli exhibited some expression of inflammatory markers (higher CD14 and CD206 expression, but CD1a, CD14, CD206, and CD11b already were present on E. coli-stimulated DCs; levels of FcεRI and CD209 on infDCs could not be confirmed in our experiments) (Supplemental Fig. 1D).…”

The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

“…Malt1 -/-mice were originally generated in our laboratory (20,37) and backcrossed for more than 10 generations into the C57BL/6 backIn vitro, IL-6, IL-21, and IL-23 -with or without TGF-β -have been reported to induce Th17 cell differentiation or stabilization (5,11,12,44,45). However, the roles of TCR stimulation and costimulatory signaling in the differentiation of specific Th subsets have yet to be clearly delineated (46)(47)(48)(49). Engagement of both the TCR and CD28 results in activation of the IKK complex, which relieves NF-κB from its suppression by the IκB proteins.…”