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  • GPR also known as EBI

    2020-01-17

    GPR183 (also known as EBI2) is a Gαi-coupled seven-transmembrane chemotactic receptor. It is highly expressed on follicular B cells, CD4+ dendritic cells (DCs), and CD4+ T cells but is downregulated on germinal center (GC) 3X FLAG Peptide sale in secondary lymphoid organs and controls cell migration to achieve efficient antibody responses and CD4+ T cell responses (Gatto et al., 2009, Gatto et al., 2013, Li et al., 2016, Pereira et al., 2009, Yi and Cyster, 2013, Yi et al., 2012). GPR183 ligand, 7α,25-dihydroxycholesterol (7α,25-OHC), is produced by stromal cells residing in the interfollicular regions of lymph nodes (LNs) and the bridging channels of the spleen (Hannedouche et al., 2011, Liu et al., 2011, Yi et al., 2012). GPR183 expressed on CD4+ ILC3s (also termed as lymphoid tissue inducer cells [LTis]) controls their migration and the formation of colonic tertiary lymphoid organs (Emgård et al., 2018). However, whether GPR183 and 7α,25-OHC control the accumulation, distribution, and tissue-protective function of ILC3s in the gut-associated lymphoid tissues and in the intestinal lamina propria (LP) has not been examined. In this study, we demonstrate that ILC3s isolated from the mesenteric LNs (mLNs) and intestinal LP express GPR183 and intestinal ILC3s migrate toward 7α,25-OHC in vitro. Quantitative PCR (qPCR) analysis indicated 7α,25-OHC production by gut stromal cells, and genetic deletion of GPR183 or 7α,25-OHC resulted in a disorganized accumulation of ILC3s in the subcapsular sinus of the mLNs and reduced ILC3 accumulation in the intestine. The regulation of ILC3 accumulation in the intestine by GPR183 was ILC3 intrinsic and was required for optimal IL-22 production and protective immunity against the enteric bacterium, Citrobacter rodentium (C. rodentium). Taken together, these data reveal a previously unrecognized role of the GPR183-7α,25-OHC pathway in regulating ILC3-dependent immunity to enteric bacterial infection.
    Results
    Discussion Mucosal barriers are constitutively challenged by various stimuli, and the homeostasis of mucosal barriers both at steady state and upon challenge are maintained by tissue-resident immune cells (Kurashima et al., 2013, Okumura and Takeda, 2016). ILC3s are found in lymphoid tissues and are enriched in the intestine, where they play critical roles in regulating adaptive immune responses against commensal bacteria, as well as in innate immunity against enteric bacterial infections (Hepworth et al., 2013, Hepworth et al., 2015, Rankin et al., 2016, Satoh-Takayama et al., 2008, Sawa et al., 2011, Song et al., 2015, Sonnenberg et al., 2011). Although the mechanisms ILC3s employ to control infections and promote tissue repair continue to be defined (Satoh-Takayama et al., 2008, Sawa et al., 2011, Sonnenberg et al., 2011), our understanding of how the accumulation, distribution, and tissue-protective function of ILC3s in the intestine and its associated lymphoid organs are controlled remained limited. Emgård et al. (2018) recently reported that CD4+ LTi-like ILC3s express GPR183 that controls cell migration and formation of solitary intestinal lymphoid tissues in the colon and enhances IL-22 production by ILC3s in the colon at steady state. In the current study, we demonstrate that GPR183 is expressed on murine and human ILC3s and that GPR183 and its ligand 7α,25-OHC regulate the accumulation and distribution of ILC3s in lymphoid tissues and the intestine, and consequently, GPR183 controls ILC3-dependent innate immunity and tissue protection following enteric bacterial infection. We also identify GPR183-dependent accumulation of IL-22-producing ILC3s in the intestine following C. rodentium infection. Of note, enhanced IL-22 production by ILC3s was not detectable, possibly due to heightened inflammation elicited by the bacterial infection. ILC3s reside in the interfollicular areas of the mLNs, where they present commensal bacterial antigen through major histocompatibility complex class II and prevent CD4+ T cell-induced chronic intestinal inflammation toward commensal bacteria (Hepworth et al., 2015). In this study, we show that GPR183 controls the distribution of ILC3s in mLNs. GPR183-deficient ILC3s accumulated in the outer regions of the interfollicular areas, which are close to the subcapsular sinuses. DCs migrate into the LNs via the lymph through subcapsular sinuses and then move to the paracortex where they interact with helper T cells (Lian and Luster, 2015). This pathway is regulated by CCR7, a molecule that also controls the accumulation of ILC3s to LNs (Lian and Luster, 2015, Mackley et al., 2015). Similarly, ILC3s migrate from other organs, such as the intestine (Mackley et al., 2015), and enter the LNs through subcapsular sinuses. In the context of GPR183 deficiency, ILC3s cannot migrate into the interfollicular areas because they fail to respond to the ligand expressed in the inner regions of the interfollicular areas and hence are sequestered in the subcapsular sinuses. As GPR183 plays such important roles in regulating the distribution and function of ILC3s in both lymphoid and non-lymphoid tissues, GPR183 itself and its oxysterol ligand-producing pathway could be potential therapeutic targets for controlling and regulating ILC3 functions in multiple infectious and inflammatory diseases.