Distinct Roles for CXCR6+ and CXCR6− CD4+ T Cells in the Pathogenesis of Chronic Colitis

Mandai, Yasushi; Takahashi, Daisuke; Hase, Koji; Obata, Yuichi; Furusawa, Yukihiro; Ebisawa, Masashi; Nakagawa, Tomoo; Satô, Tôru; Katsuno, Tatsuro; Saitō, Yasushi; Shimaoka, Takeshi; Yokosuka, Osamu; Yokote, Kotaro; Ohno, Hiroshi

doi:10.1371/journal.pone.0065488

Cited by 24 publications

(16 citation statements)

References 29 publications

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“…Relatedness is suggested also for IL17/IFNγ DP cells that emerge in an IL-23-dependent fashion in murine inflammatory bowel disease (55). In a T cell transfer model of chronic colitis, pathogenic CD4 cells marked by CXCR6 include IL-17/IFNγ DP cells along with predominant IL-17 SP and IFNγ SP cells (56); poor proliferation characterizes these cells and thus distinguishes them from the rapidly proliferating CXCR6 + TH cells in EAE. Lastly, encephalitogenic CXCR6 + TH cells have at least one feature, cytotoxic granules, in common with CD4 + cytolytic T cells (CD4 + CTL) that provide, e.g., antiviral protection.…”

Section: Discussionmentioning

confidence: 94%

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

Hou

Rao

Yuki

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17–expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1−/− mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1−/− mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.

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Section: Discussionmentioning

confidence: 94%

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

Hou

Rao

Yuki

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The CXCL16 gene is located within the Idd4 T1D risk locus in mouse (27), and CXCR6 is located within the IDDM22 T1D disease locus in man, making this chemokine-receptor pair of strong potential interest (28). This pathway also interested us since CXCR6 has been shown to have a role for trafficking of pathogenic T cells in other animal models of autoimmunity such as EAE and colitis (42–44). CXCL16 has also been shown to be elevated in EAE and during rejection of a transplant (42, 45–47).…”

Section: Resultsmentioning

confidence: 99%

CD11c+ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes

et al. 2019

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Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that affects more than 19 million people with incidence increasing rapidly worldwide. For T cells to effectively drive T1D, they must first traffic to the islets and extravasate through the islet vasculature. Understanding the cues that lead to T cell entry into inflamed islets is important because diagnosed T1D patients already have established immune infiltration of their islets. Here we show that CD11c+ cells are a key mediator of T cell trafficking to infiltrated islets in non-obese diabetic (NOD) mice. Using intravital 2-photon islet imaging we show that T cell extravasation into the islets is an extended process, with T cells arresting in the islet vasculature in close proximity to perivascular CD11c+ cells. Antigen is not required for T cell trafficking to infiltrated islets, but T cell chemokine receptor signaling is necessary. Using RNAseq, we show that islet CD11c+ cells express over 20 different chemokines that bind chemokine receptors expressed on islet T cells. One highly expressed chemokine-receptor pair is CXCL16-CXCR6. However, NOD. CXCR6−/− mice progressed normally to T1D and CXCR6 deficient T cells trafficked normally to the islets. Even with CXCR3 and CXCR6 dual deficiency, T cells trafficked to infiltrated islets. These data reinforce that chemokine receptor signaling is highly redundant for T cell trafficking to inflamed islets. Importantly, depletion of CD11c+ cells strongly inhibited T cell trafficking to infiltrated islets of NOD mice. We suggest that targeted depletion of CD11c+ cells associated with the islet vasculature may yield a therapeutic target to inhibit T cell trafficking to inflamed islets to prevent progression of T1D.

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“…It has been suggested that on CD4 ϩ T cells, CXCR6 serves as an extralymphoid homing receptor (54), and limited studies in humans suggest that it is expressed mainly by memory T cells, particularly T cells in tissues such as lung and at sites of inflammation and cancer (55)(56)(57), although expression on naive cells has been reported as well (58). Studies of CXCR6 expression on nonhuman primate natural host cells have been hindered by a lack of cross-reactivity of anti-human CXCR6 antibodies.…”

Section: Discussionmentioning

confidence: 99%

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

Wetzel

Elliott

et al. 2017

J Virol

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African green monkeys (AGM) and sooty mangabeys (SM) are wellstudied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro. Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4 ϩ T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function.IMPORTANCE Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmacmacaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4 ϩ cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expression level is low, the use of CXCR6 or other coreceptors to

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Distinct Roles for CXCR6+ and CXCR6− CD4+ T Cells in the Pathogenesis of Chronic Colitis

Cited by 24 publications

References 29 publications

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

CD11c+ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

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