Cutting Edge: ICOS-Deficient Regulatory T Cells Display Normal Induction of Il10 but Readily Downregulate Expression of Foxp3

Abstract

The ICOS pathway has been implicated in the development and functions of regulatory T (Treg) cells, including those producing IL-10. Treg cell-derived IL-10 is indispensable for the establishment and maintenance of intestinal immune homeostasis. We examined the possible involvement of the ICOS pathway in the accumulation of murine colonic Foxp3-and/or IL-10expressing cells. We show that ICOS deficiency does not impair induction of IL-10 by intestinal CD4 T cells but, instead, triggers substantial reductions in gut-resident and peripherally derived Foxp3 + Treg cells. ICOS deficiency is associated with reduced demethylation of Foxp3 CNS2 and enhanced loss of Foxp3. This instability significantly limits the ability of ICOS-deficient Treg cells to reverse ongoing inflammation. Collectively, our results identify a novel role for ICOS costimulation in imprinting the functional stability of Foxp3 that is required for the retention of full Treg cell function in the periphery.

ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

“…Thus we had WT, YF, and KO mice whose T R expressed monomeric red fluorescent protein (RFP) under control of the Foxp3 locus, faithfully marking T R without the need for intracellular Foxp3 staining (44). In line with published data, we found a ~30% reduction in the frequency and number of T R in the spleens of KO compared to WT mice (24,34) Fig. 1A] and intact MAPK signaling (43), we saw a similar reduction in splenic T R abundance in YF mice, indicating that activation of PI3K signaling is the critical pathway by which ICOS regulates T R abundance [ Fig.…”

“…CD4 + T cells from KO mice are capable of producing WT levels of IL-10 in vitro, and interestingly, appear to produce more IL-10 than WT counterparts under T H 2-polarizing conditions (33). Furthermore, recent studies assessing T R in the brain during chronic Toxoplasma gondii infection and lamina propria T R at baseline report no changes in IL-10 production in the presence or absence of ICOS signaling (34,59). Therefore, the reduction in IL-10 + T R with ICOS blockade observed in specific in vivo models is likely due to insufficient activation or access to specific environmental cues within tissues rather than an inherent requirement for ICOS signaling to drive IL-10 production.…”

“…ICOS signaling is implicated in IL-10 production both in vitro and in vivo (23,26,27,(30)(31)(32)(33)(34)(35)(36). Surprisingly, compared to VAT-T R from WT mice, a substantially higher frequency of YF and KO VAT-T R were poised to produce IL-10 upon ex vivo stimulation with PMA/I, with no appreciable differences in IL-10 expression by splenic T R [Fig.…”

“…ICOS costimulation in vitro super-induces IL-10 expression (26,27), and this depends on its ability to activate phosphoinositide 3-kinase (PI3K) (28,29). Although mice deficient in ICOS or ICOS ligand do not develop spontaneous inflammatory or autoimmune disease, genetic or antibody-mediated blockade of ICOS signaling promotes inflammatory immune responses in mouse models of autoimmunity and infection as a result of reduced T R abundance and/or IL-10 production (23,(30)(31)(32)(33)(34)(35)(36).…”

Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

“…Co-receptors were selected from CD28 or TNFR family proteins ( Figure 1A) since these are functionally relevant in T cells and, in some cases, had already been successfully used as CARs in Tconvs. Within the CD28 family, in addition to the wild type (wt) CD28 protein, which is known to be important for Treg activation and proliferation (Golovina et al, 2008;Tai et al, 2005;Zhang et al, 2013) we selected: CD28(Y173F), a point mutant with diminished PI3K pathway activity which may be beneficial for Treg function (Okkenhaug et al, 2001); ICOS, which is important in Treg survival and may be involved in IL-10 production (Kornete et al, 2012;Landuyt et al, 2019;Redpath et al, 2013); CTLA-4, which is essential for Treg function (Esensten et al, 2016;Walker and Sansom, 2011); CTLA-4 (Y165G), a point mutant with increases cell surface expression (Nakaseko et al, 1999); and PD-1, which is essential for generation and maintenance of peripherally-induced Tregs .…”