As is reported, group 2 innate lymphoid cells (ILC2s), which resemble Th2 cells, are capable of producing copious amounts of the type 2 cytokines IL-5 and IL-13 and are responsible for the development of allergic respiratory inflammation (126). and the holistic role of ICOS toward the immune system will help to improve the therapeutic schedule of diseases. (18). In addition, NF-B also plays an essential role in Treg identity and function, among which two canonical subunits are c-Rel and RelA (p65). NF-B c-Rel is critical for thymic Treg development, and it was also shown to be important for the function of activated Tregs, as a number of genes associated with homeostasis and function of aTregs were dramatically downregulated in c-Rel-deficient Tregs, whereas RelA (p65) mediates the development, survival, and function of eTregs (19C21). RelA-deficient Tregs were observed to show a significant reduction in the expression of eTreg signature genes, such as and (Helios) site, indicating that they are derived from pTregs (27C29). Additionally, these colonic RORt+ Tregs were shown to be relative stable, although they were observed to loss FOXP3 expression slightly higher than FOXP3+ Tregs when transferred to lymphopenic mice together with na?ve T cells, and to be necessary to maintain colonic homeostasis, displaying a superior regulatory capacity to prevent colitis (27). Moreover, these colonic RORt+ Tregs express IL-10 but few IL-17+ cells even in inflamed colon (27, 28). However, consistent with the idea that strong self-antigen stimulation could promote the loss of FOXP3 expression in Tregs, thus favoring ex-Treg formation in inflammatory setting, (30) a large number of transferred CBir1-specific FOXP3+ Tregs in TCRxC/C mice that were induced by culturing na?ve CD4+ T cells in the presence of TGF- lost FOXP3 expression and converted to IFN-+/IL-17+ T cells, and a fraction of transferred cells obtained IL-17+/IFN-+ Treg phenotype (31). This phenomenon could also be partly explained by their use of induced Tregs (iTregs) in the experiments, as iTregs are less stable than tTregs to maintain FOXP3 expression due to conserved non-coding DNA sequence (CNS) 2 CpG island hypermethylation (32). Additionally, although these CBir1-specific Foxp3+IFN-+ T cells retained suppressive ability, it was observed that these AM 1220 FOXP3+IFN-+ T cells can differentiate into IFN-+ T cells ultimately (31). Similarly, CD4+FOXP3+IL-17A+ T cells in the dermis of lesional skin and an enhanced propensity of purified peripheral blood Tregs to convert to IL-17A+ T cells after stimulation compared with healthy individuals have been shown AM 1220 in severe psoriatic patients (33). Therefore, it is hard to say whether the stability and the inhibitory capacity of ICOS+IFN-+/IL-17+ Tregs that are observed in both the steady state and inflammatory condition are still retained. Activated eTregs have been shown to be less stable than cTregs to maintain FOXP3 expression and ICOS-induced higher PI3K signaling also contributes to this instability (34, 35). The stability and function of these specific ICOS+ Tregs need further detailed inspection. The Role of ICOS Signaling in Tregs According to various studies, ICOS is generally involved in the production, proliferation and survival of Tregs, providing them a strong suppressive capability, which we will discuss separately below. First, ICOS can mediate the generation of FOXP3+ Tregs. Compared with healthy individuals, CD4+CD25C T cells from a small subset of common variable immunodeficiency (CVID) patients who have a homozygous genomic deletion of ICOS cannot induce anergic T cells with immature myeloid DCs, (36) which are involved in maintaining peripheral tolerance by the induction of Tregs (37). Furthermore, the ablation of ICOS in unmanipulated mice was shown to result in a reduced number of FOXP3+ Tregs compared to that observed in WT mice (38, 39). Blockage of ICOS-ICOSL ligation when culturing human na?ve CD4+ T cells with CD40-activated B cells was also shown to decrease FOXP3 levels, thereby impairing the generation of FOXP3+ Rabbit polyclonal to PAWR Tregs (40). These phenomena confirm the importance AM 1220 of ICOS for the transcriptional activity of CNS2 may be another reason for the reduction of Tregs (14). However, the reduced frequency of FOXP3+ Tregs in the periphery should not be attributed to the dysfunction of the thymus, as (9). When immunizing stimulation culture in the presence of IL-2, purified mouse ICOS+ Tregs from lymph node and spleen expressed a higher level of Bcl-2, an anti-apoptotic molecule belonging to the Bcl-2 super family, than ICOSC Tregs (42). But the higher expression of Bcl-2 in ICOS+ Tregs could also be partly explained by the addition of IL-2, as Bcl-2 is known to be sensitive to IL-2 AM 1220 stimulation, and ICOSC Tregs usually do not react to IL-2 like ICOS+ Tregs and for that reason usually do not upregulate Bcl-2 appearance (42). Indeed, Compact disc44hiCD62Llo eTregs that exhibit high degrees of ICOS display low Bcl-2 appearance under steady condition conditions, and these Bcl-2lo eTregs selectively had been observed to become.