ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases

Abstract

Recent studies have reported the pathological effect of ICOS⁺ T cells, but ICOS signals also widely participate in anti-inflammatory responses, particularly ICOS⁺ regulatory T (Treg) cells. The ICOS signaling pathway endows Tregs with increased generation, proliferation, and survival abilities. Furthermore, there is enough evidence to suggest a superior capacity of ICOS⁺ Tregs, which is partly attributable to IL-10 induced by ICOS, yet the associated mechanism needs further investigation. In this review, we discuss the complicated role of ICOS⁺ Tregs in several classical autoimmune diseases, allergic diseases, and cancers and investigate the related therapeutic applications in these diseases. Moreover, we identify ICOS as a potential biomarker for disease treatment and prognostic prediction. In addition, we believe that anti-ICOS/ICOSL monoclonal antibodies exhibit excellent clinical application potential. A thorough understanding of the effect of ICOS⁺ Tregs and the holistic role of ICOS toward the immune system will help to improve the therapeutic schedule of diseases.

Keywords: ICOS; Treg cells; autoimmune disease; immunotherapy; neoplasm.

FIGURE 1

Production of IL-10 by ICOS-expressing T cells with regulatory function. CD4⁺ICOS⁺ Tregs express high levels of IL-10 but smaller amounts of TGF-β compared with ICOS^– Tregs. Transcriptome and FACS analyses have demonstrated a correlation between the increased ICOS expression on Tregs with the high expression levels of CD5, CD69, CXCR3, and T-bet as well as some checkpoint inhibitors, such as CTLA-4, TIGIT, Lag3, and PD-1, (15, 56, 57) some of which have been shown to promote the transcription of the IL-10 gene, contributing to high levels of IL-10 secretion together with ICOS. In addition, other ICOS-expressing regulatory cells, such as Tr1, Treg-of-B cells, and Tfr cells, can also be the source of IL-10.

FIGURE 2

ICOS signaling pathway in Tregs. ICOS-ICOSL interaction promotes the generation, proliferation, survival and suppressive ability of regulatory T cells (Tregs) through complex signaling pathways. First, activation of ICOS promotes Foxp3 transcription, favoring NFAT binding to FOXP3 over AP-1 and upregulating FOXP3 downstream regulatory genes, such as Il-10 and Tgf-β. Second, ICOS engagement induces PI3K recruitment to the YMFM motif at the cytoplasmic tail and the phosphorylation of Akt. Activation of Akt can induce Bcl-2 expression and inhibit pro-apoptotic Bcl-2 family protein production, thereby promoting ICOS⁺ Treg survival. Furthermore, ICOS also activates the mTORC1 signals, which is suggested to mediate protein synthesis and metabolism in Tregs. In addition, ICOS expression elevates CXCR3 expression, which promotes the migration of Tregs to inflammatory tissues.