The roles of CCR6 in migration of Th17 cells and regulation of effector T-cell balance in the gut

Migration and trafficking receptors of Th17 cells to mucosal tissues have been unclear. We report that Th17 cells preferentially migrate to the intestine and associated lymphoid tissues, and CCR6 is the homing receptor important for Th17 cell migration to certain tissue microenvironments of the intestine such as Peyer's patches and other sites where its ligand CCL20 is expressed. We found the cytokine transforming growth factor-β1 is required for CCR6 expression whereas IL-2 suppresses it. CCR6-deficient Th17 cells aberrantly migrate to different compartments of the intestine. Surprisingly, administration of CCR6-deficient Th17 cells into severe combined immunodeficiency (SCID) mice led to excessive intestinal inflammation with increased Th1 but decreased Th17 cells and FoxP3⁺ T cells. In addition, CCR6 deficiency led to aberrantly widespread effector T cells in the inflamed intestine of the SCID mice. We conclude that CCR6 regulates Th17 cell migration to the gut and effector T-cell balance/distribution in inflamed intestine.     

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9-CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model, we showed that CCR9⁺ dendritic cells (DCs) specifically CD11b⁻CD103⁺ DCs were significantly increased in the gut-associated lymphoid tissues (GALT) compared to control mice. These CCR9⁺ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency-associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9⁺ DCs promoted in vitro differentiation of Foxp3⁺ regulatory CD4⁺ T cells (Tregs). CCL25-induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4⁺ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL-10. Furthermore, adoptive transfer of CCR9⁺ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA-specific gut-allergic response. Our results suggest CCR9⁺ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.     

CCR6 defines a subset of activated memory T cells of Th17 potential in immune thrombocytopenia

Current researches have determined the significance of C-C chemokine receptor (CCR)6 expression as either a marker of T helper cells (Th) or an effector and regulator of T cell function. However, the roles of CCR6 in the pathogenesis of immune thrombocytopenia (ITP) are unclear. In this study, we aimed to investigate the phenotype and functional characteristics of circulating CCR6⁺ T cells in blood from chronic ITP patients and healthy controls. We found that the frequency of CCR6⁺CD4⁺ cells was higher in ITP patients than in healthy controls. Anti-CD3/anti-CD28 stimulation induced rapid expansion of CCR6⁺CD4⁺ cells in ITP patients. CCR6⁺CD4⁺ cells had a phenotype of activated cells and predominantly expressed CD45RO. Forkhead box protein P3 (FoxP3) and CD25-positive cells were exclusively detected within the CCR6⁺CD4⁺ cells. In ITP patients, CCR6⁺ regulatory T cells (T_reg) were decreased and positively correlated with platelet counts and transforming growth factor (TGF)-β plasma levels. In contrast to CCR6^– counterparts, CCR6⁺CD4⁺ cells produced higher levels of interleukin (IL)-17A. The frequency of CCR6⁺ Th17 was higher in ITP patients and positively correlated with IL-17A levels in supernatant. Most importantly, CCR6⁺CD4⁺ cell subpopulations, but not CCR6⁻CD4⁺, were closely correlated to treatment response of ITP patients. These findings suggest that circulating CCR6⁺CD4⁺ cells in ITP patients have characteristics of activated memory Th17 phenotype and could be used to monitor disease activity and treatment response.     

Active CD4+ helper T cells directly stimulate CD8+ cytotoxic T lymphocyte responses in wild-type and MHC II gene knockout C57BL/6 mice and transgenic RIP-mOVA mice expressing islet β-cell ovalbumin antigen leading to diabetes

CD4⁺ helper T (Th) cells play crucial role in priming, expansion and survival of CD8⁺ cytotoxic T lymphocytes (CTLs). However, how CD4⁺ Th cell's help is delivered to CD8⁺ T cells in vivo is still unclear. We previously demonstrated that CD4⁺ Th cells can acquire ovalbumin (OVA) peptide/major histocompatibility complex (pMHC I) and costimulatory CD80 by OVA-pulsed DC (DC_OVA) stimulation, and then stimulate OVA-specific CD8⁺ CTL responses in C57BL/6 mice. In this study, we further investigated CD4⁺ Th cell's effect on stimulation of CD8 CTL responses in major histocompatibility complex (MHC II) gene knockout (KO) mice and transgenic rat insulin promoter (RIP)-mOVA mice with moderate expression of self OVA by using CD4⁺ Th cells or Th cells with various gene deficiency. We demonstrated that the in vitro DC_OVA-activated CD4⁺ Th cells (3 × 10⁶ cells/mouse) can directly stimulate OVA-specific CD8⁺ T-cell responses in wild-type C57BL/6 mice and MHC II gene KO mice lacking CD4⁺ T cells. A large amount of CD4⁺ Th cells (12 × 10⁶ cells/mouse) can even overcome OVA-specific immune tolerance in transgenic RIP-mOVA mice, leading to CD8⁺ CTL-mediated mouse pancreatic islet destruction and diabetes. The stimulatory effect of CD4⁺ Th cells is mediated by its IL-2 secretion and CD40L and CD80 costimulations, and is specifically delivered to OVA-specific CD8⁺ T cells in vivo via its acquired pMHC I complexes. Therefore, the above elucidated principles for CD4⁺ Th cells will have substantial implications in autoimmunity and antitumor immunity, and regulatory T-cell-dependent immune suppression.     

The oxysterol receptor LXRβ protects against DSS- and TNBS-induced colitis in mice

We examined the function of the oxysterol receptors (LXRs) in inflammatory bowel disease (IBD) through studying dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and by elucidating molecular mechanisms underlying their anti-inflammatory action. We observed that Lxr-deficient mice are more susceptible to colitis. Clinical indicators of colitis including weight loss, diarrhea and blood in feces appeared earlier and were more severe in Lxr-deficient mice and particularly LXRβ protected against symptoms of colitis. Addition of an LXR agonist led to faster recovery and increased survival. In contrast, Lxr-deficient mice showed slower recovery and decreased survival. In Lxr-deficient mice, inflammatory cytokines and chemokines were increased together with increased infiltration of immune cells in the colon epithelium. Activation of LXRs strongly suppressed expression of inflammatory mediators including TNFα. While LXRα had anti-inflammatory effects in CD11b⁺ immune cell populations, LXRβ in addition had anti-inflammatory effects in colon epithelial cells. Lack of LXRβ also induced CD4⁺/CD3⁺ immune cell recruitment to the inflamed colon. Expression of both LXRA and LXRB was significantly suppressed in inflamed colon from subjects with IBD compared with non-inflamed colon. Taken together, our observations suggest that the LXRs could provide interesting targets to reduce the inflammatory responses in IBD.     

Inflammasome activation has an important role in the development of spontaneous colitis

Inflammatory bowel disease (IBD) is characterized for dysregulated intestinal inflammation. Conflicting reports have shown that activation of inflammasome could promote or decrease intestinal inflammation in an acute colitis model, whereas the involvement of inflammasome activation in chronic colitis is poorly understood. In this study, we investigated the role of inflammasome activation in the development of chronic intestinal inflammation by utilizing interleukin-10 (IL-10) knockout (KO) mouse as an animal model, which develops chronic colitis resembling human IBD. We demonstrate the causative link between inflammasome activation and the development of chronic intestinal inflammation. Our results show that mature IL-1β protein levels were significantly increased in all colon sections from IL-10-deficient mice compared with that of wild-type mice. We found that inhibition of inflammasome activities with IL-1 receptor antagonist or caspase-1 inhibitors suppressed IL-1β and IL-17 production from inflamed colon explants. Furthermore, blocking inflammasome activation with caspase-1 inhibitor in vivo significantly ameliorated the spontaneous colitis in IL-10 KO mice. Taken together, these observations demonstrate that inflammasome activation promotes the development of chronic intestinal inflammation.     

Expression of CCR8 is increased in asthma

Background Chemokines and their receptors could play key roles in the recruitment of T cells to the asthmatic lung. CCR8 is preferentially expressed on T‐helper type 2 cells, and is thought to play a role in the pathogenesis of human asthma. Objective Determine the expression of CCR8 on T cells in blood, bronchoalveolar lavage (BAL) and bronchial mucosa from asthmatics and normal subjects. Methods CCR8 expression in blood and BAL from asthma and normal subjects was studied using flow cytometry. CCR8 expression on IFN‐γ⁺ and IL‐4⁺/IL‐13⁺ blood and BAL T cells was studied following stimulation with Phorbol–Myristate–Acetate and Calcium Ionophore. Paraffin‐embedded bronchial biopsies were used to study CCR8 in bronchial epithelium. Results The percentage of CD3⁺ cells expressing CCR8 in the blood was higher in asthmatics (4.7±0.4%) compared with normal subjects (3.0±0.4%; P<0.01). There was an approximately sixfold enrichment of CCR8 on IL‐4⁺/IL‐13⁺ cells compared with IFN‐γ⁺ T cells (P<0.001) in both asthmatic and normal subjects in both blood and BAL. Significantly more BAL T cells expressed CCR8 in asthmatic (8.6±0.8%) compared with normal subjects (3.9±0.7%) (P<0.01). In paired blood‐BAL samples from asthmatics, significantly more CCR8+CD3⁺ T cells were present in BAL (9.0±0.9%) than in blood (5.6±0.9%; P<0.05). There were more CCR8‐positive cells in bronchial biopsies from asthmatic (93±11 cells/mm²) compared with normal subjects (30±16 cells/mm²) (P<0.05). The ligand CCL1 was increased in the BAL of asthmatics compared with normal subjects (35±6 vs. 12.9±7 pg/mL; P<0.05). Conclusion There may be a role for CCR8 in the recruitment of T cells to the lung in asthmatics. Cite this as: K. Mutalithas, C. Guillen, C. Raport, R. Kolbeck, D. Soler, C. E. Brightling, I. D. Pavord and A. J. Wardlaw, Clinical & Experimental Allergy, 2010 (40) 1175–1185.     

CCR6− regulatory T cells blunt the restoration of gut Th17 cells along the CCR6–CCL20 axis in treated HIV-1-infected individuals

The gut CD4⁺ T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6–CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6⁺CD4⁺ T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3⁺ T regulatory (Treg) cells, specifically the CCR6⁻ subset, was increased. The resulting imbalance in the Th17/CCR6⁻ Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-β (TGF-β) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6⁺CD4⁺ T cells to the small intestine in treated HIV-1-infected individuals.     

Protein kinase 2 (CK2) controls CD4+ T cell effector function in the pathogenesis of colitis

Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD), is characterized by chronic inflammation of the gastrointestinal tract and associated with aberrant CD4⁺ T-helper type 1 (Th1) and Th17 responses. Protein kinase 2 (CK2) is a conserved serine–threonine kinase involved in signal transduction pathways, which regulate immune responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3⁺ regulatory T cells. The function of CK2 in CD4⁺ T cells during the pathogenesis of CD is unknown. We utilized the T cell-induced colitis model, transferring CD45RB^hi-naive CD4⁺ T cells from CK2α^fl/fl controls and CK2α^fl/fldLck-Cre mice into Rag1^−/− mice. CD4⁺ T cells from CK2α^fl/fldLck-Cre mice failed to induce wasting disease and significant intestinal inflammation, which was associated with decreased interleukin-17A-positive (IL-17A⁺), interferon-γ-positive (IFN-γ⁺), and double-positive IL-17A⁺IFN-γ⁺ CD4⁺ T cells in the spleen and colon. We determined that CK2α regulates CD4⁺ T cell proliferation through a cell-intrinsic manner. CK2α is also important in controlling CD4⁺ T cell responses by regulating NFAT2, which is vital for T cell activation and proliferation. Our findings indicate that CK2α contributes to the pathogenesis of colitis by promoting CD4⁺ T cell proliferation and Th1 and Th17 responses, and that targeting CK2 may be a novel therapeutic treatment for patients with CD.     

CD4+CCR6+ T cells,but not γδ T cells,are important for the IL-23R-dependent progression of antigen-induced inflammatory arthritis in mice

IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL-23R⁺ T cells are critical in driving T cell-mediated synovitis. We demonstrate, using knock-in IL-23R-GFP reporter (IL-23R^GFP/+) mice, that CD4⁺CCR6⁺ T cells and γδ T cells, but not CD8⁺ T cells, express the IL-23R(GFP). During early arthritis, IL-23R(GFP)⁺CD4⁺CCR6⁺ T cells, but not IL-23R(GFP)⁺ γδ T cells, were present in the inflamed joints. IL-23R^GFP/+ mice were bred as homozygotes to obtain IL-23R^GFP/GFP (IL-23R deficient/IL-23R^−/−) mice, which express GFP under the IL-23R promotor. Arthritis progression and joint damage were significantly milder in IL-23R^−/− mice, which revealed less IL-17A⁺ cells in their lymphoid tissues. Surprisingly, IL-23R^−/− mice had increased numbers of IL-23R(GFP)⁺CD4⁺CCR6⁺ and CCR7⁺CD4⁺CCR6⁺ T cells in their spleen compared to WT, and IL-23 suppressed CCR7 expression in vitro. However, IL-23R(GFP)⁺CD4⁺CCR6⁺ T cells were present in the synovium of IL-23R^−/− mice at day 4. Finally, adoptive transfer experiments revealed that CD4⁺CCR6⁺ T cells and not γδ T cells drive arthritis progression. These data suggest that IL-23R-dependent T cell-mediated synovitis is dependent on CD4⁺CCR6⁺ T cells and not on γδ T cells.     

Spontaneous Development of Autoimmune Uveitis Is CCR2 Dependent

Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow–derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4⁺ T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity.Uveitis ranks third among causes of blindness in the United States; however, the mechanisms of pathogenesis are largely unknown. Clinically, the most common form of sight-threatening uveitis is posterior uveitis associated with systemic autoimmune disease, in which noninfectious intraocular inflammation is characterized by severe infiltration by T cells and macrophages.^1,2 Because current approaches for treating posterior uveitis rely on general suppression of the immune system, there is urgent need for more specific treatments with fewer adverse effects. Identifying therapeutic targets (ie, specific immune mediators involved in the pathogenesis of autoimmune uveitis) is key to discovering effective treatments.Monocyte recruitment to the inflamed tissue is a common manifestation and essential cause of many inflammatory diseases. The C-C chemokine receptor type 2 protein (CCR2) plays a critical role in regulation of monocyte trafficking into inflamed tissues, through interactions with ligands belonging to the family of proinflammatory monocyte chemotactic proteins (MCPs).³ CCR2 is reported to be critical in the efficient recruitment of monocytes in experimental autoimmune encephalomyelitis,⁴ thioglycollate-induced peritonitis,^5,6 and atherosclerosis.⁷ CCR2 has also been implicated in neuroinflammatory processes of degenerative central nervous system diseases such as Alzheimer disease,⁸ ischemic neuropathy,⁹ and multiple sclerosis.¹⁰ In the eye, macrophage infiltration has been reported to contribute to the pathogenesis of choroidal neovascularization,¹¹ retinitis pigmentosa,¹² and dry eye associated with autoimmune disease.¹³ Blockade of macrophage recruitment using the CCR2 antagonist INCB3344 effectively inhibited the formation of choroidal neovascularization in mice,¹⁴ and CCR2 knockdown alleviated photoreceptor death in a mouse model of inherited retinal degeneration.¹²We investigated the contribution and functional significance of CCR2 in directing monocyte and T-cell recruitment to provoke retinal inflammation in a spontaneous mouse model of autoimmune-mediated uveitis. Current murine models used to mimic immune-mediated uveitis in humans involve experimental induction by immunization with retinal autoantigens, such as interphotoreceptor retinoid-binding protein (IRBP), S-arrestin (retinal S-antigen), or endotoxin lipopolysaccharide. The IRBP-induced experimental autoimmune uveitis (EAU) model in mice is a recognized and extensively studied model of human posterior uveitis.^15,16 Dagkalis et al¹⁷ found that CCR2 knockdown did not reduce the severity of disease or the percentage of monocytes recruited to the site of retinal inflammation. Despite a significant number of infiltrating macrophages in the retinal tissues of EAU mice, the authors concluded that CCR2 does not have a primary role in the recruitment of monocytes to the inflammatory site across the blood–retina barrier in well-developed EAU.In the present study, we revisited the role of CCR2-expressing cells in the pathogenesis of noninfectious posterior uveitis, using an alternative model of ocular autoimmune disease. Mice deficient in the autoimmune regulator gene Aire provide a model of spontaneous, organ-specific, CD4⁺ T-cell–mediated autoimmune uveitis that closely mimics human endogenous uveitis. Aire knockout (Aire KO) mice develop immune infiltrates in the posterior chamber of the eye that are reminiscent of those seen in the induced rodent model of EAU.¹⁸ Aire-deficient mice develop uveitis as a result of loss of thymic expression of a single eye antigen, IRBP. Lack of IRBP expression solely in the thymus, even in the presence of Aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity. Autoantibodies specific to IRBP are found within the photoreceptor layer of the retina,¹⁹ where they initiate or trigger retinal inflammation and photoreceptor destruction. Alongside the equine recurrent uveitis model²⁰ and the recently developed IRBP T-cell receptor transgenic mouse (R161H),²¹ Aire KO mice represent a unique, spontaneous animal model of autoimmune uveitis and thereby provide an efficient model to recapitulate clinical and immunopathological aspects of the human disease.In the present study, we demonstrate monocytic and lymphocytic infiltration of the neuroretina in the eyes of Aire KO mice. Our findings from genetic knockdown and bone-marrow chimera models suggest that the recruitment of monocytes and T cells to the inflamed retina of Aire KO mice is CCR2 dependent. Accordingly, CCR2-deficient bone marrow cells effectively rescue the neuroretina from destruction in Aire KO chimeras. These results provide evidence that CCR2-expressing bone marrow–derived mononuclear cells induce uveitis through the recruitment of autoreactive CD4⁺ T cells. Delineating the underlying immune events that provoke uveitis in the setting of autoimmune disease is an essential step toward developing novel treatments. Our findings point to CCR2-expressing cells as promising therapeutic targets in the management of autoimmune uveitis.     

Critical role of CCL22/CCR4 axis in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α+ CD103+ dendritic cells

Macrophages and dendritic cells (DCs) in murine spleen are essential for the maintenance of immune homeostasis by elimination of blood‐borne foreign particles and organisms. It has been reported that splenic DCs, especially CD8α⁺ CD103⁺ DCs, are responsible for tolerance to apoptosis‐associated antigens. However, the molecular mechanism by which these DCs maintain immune homeostasis by blood‐borne apoptotic cell clearance remains elusive. Here, we found that the CCL22/CCR4 axis played a critical role in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α⁺ CD103⁺ DCs. The present results revealed that systemic administration of apoptotic cells rapidly induced a large number of CCL22 and CCR4⁺ regulatory T (Treg) cells in the spleen of C57BL/6J mice. Further study demonstrated that CD8α⁺ CD103⁺ DCs dominantly produce much higher CCL22 than CD8α⁺ CD103^? DCs. Moreover, the transient deletion of CD8α⁺ CD103⁺ DCs caused a decrease in CCL22 levels together with CCR4⁺ Treg cell percentage. Subsequently, the levels of some pro‐inflammatory cytokines, such as interleukin‐17 and interferon‐γ in the spleen with the absence of CD8α⁺ CD103⁺ DCs increased in response to the administration of apoptotic cells. Hence, intravenous injection of apoptotic cells induced a subsequent increase in CCL22 expression and CCR4⁺ Treg cells, which contribute to the maintenance of immune homeostasis at least partially by splenic CD8α⁺ CD103⁺ DCs.     

Upregulated IL-17A secretion and CCR6 co-expression in Treg subsets are related to the imbalance of Treg/Th17 cells in active UC patients

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease, which is characterized with overactive immune response. It is well established that the imbalance between Tregs and Th17 cells plays a pivotal role in pathogenesis of UC. In this study, we investigated the impact of functional changes in Treg subsets on Treg/Th17 ratio and further explored their clinical significance in the activity of UC. Treg subsets were comprehensively analysed using flow cytometry and in vitro cultured in both active and remission UC patients, of which nine active UC patients were further followed up. The correlation analyses were performed to explore the potential associations between Treg subsets and clinical indicators, as well as the impact of serum cytokines, detected by ELISA, on IL-17A secretion and CCR6 co-expression of Treg subsets. In active UC patients, we found CD45RA^-FoxP3^hiTregs were obviously decreased and inversely correlated with disease activity, while CD45RA⁺FoxP3^loTregs were increased and positively correlated with disease activity. Meanwhile, IL-17A secretion and CCR6 co-expression levels in Tregs were significantly increased in active UC. Moreover, Tregs co-expressing CCR6 possesses higher level of IL-17A secretion. In nine followed up patients, we observed downregulated IL-17A secreting and CCR6 co-expression when achieving remission from active stage. In addition, IL-17A⁺FoxP3⁺ and IL-17A⁺FoxP3⁺CCR6⁺Tregs were positively correlated with serum IL-21 and disease activity, respectively. These findings suggested that upregulated IL-17A secretion and CCR6 co-expression in Treg subsets may be related to the imbalance between Tregs and Th17 cells and associated with the disease activity in UC patients.     

TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition

TL1A is a proinflammatory cytokine, which is prevalent in the gut. High TL1A concentrations are present in patients with inflammatory bowel disease (IBD) and in IBD mouse models. However, the role of TL1A during steady‐state conditions is relatively unknown. Here, we used TL1A knockout (KO) mice to analyse the impact of TL1A on the intestinal immune system and gut microbiota. The TL1A KO mice showed reduced amounts of small intestinal intraepithelial TCRγδ⁺ and CD8⁺ T cells, and reduced expression of the activating receptor NKG2D. Moreover, the TL1A KO mice had significantly reduced body weight and visceral adipose tissue deposits, as well as lower levels of leptin and CXCL1, compared with wild‐type mice. Analysis of the gut microbial composition of TL1A KO mice revealed a reduction of caecal Clostridial cluster IV, a change in the Firmicutes/Bacteroidetes ratio in caecum and less Lactobacillus spp. in the mucosal ileum. Our results show that TL1A deficiency impacts on the gut microbial composition and the mucosal immune system, especially the intraepithelial TCRγδ⁺ T‐cell subset, and that TL1A is involved in the establishment of adipose tissue. This research contributes to a broader understanding of TL1A inhibition, which is increasingly considered for treatment of IBD.     

CCR6-CCL20 axis as a therapeutic target for autoimmune diseases

Chemokine receptor CCR6 is expressed on various cells such as B cells, immature dendritic cells, innate lymphoid cells (ILCs), regulatory CD4 T cells, and Th17 cells. CCL20 is the only known high-affinity ligand that binds to CCR6 and drives CCR6⁺ cells' migration in tissues. CCL20 is mainly produced by epithelial cells, and its expression is increased by several folds under inflammatory conditions. Genome-wide association studies (GWAS) in patients with inflammatory bowel disease (IBD), psoriasis (PS), rheumatoid arthritis (RA), and multiple sclerosis (MS) showed a very strong correlation between the expression of CCR6 and disease severity. It has been shown that disruption of CCR6-CCL20 interaction by using antibodies or antagonists prevents the migration of CCR6 expressing immune cells at the site of inflammation and reduces the severity of the disease. This review discussed the importance of the CCR6-CCL20 axis in IBD, PS, RA, and MS, and recent advances in targeting the CCR6-CCL20 in controlling these autoimmune diseases.     

Changes in histone acetylation and methylation that are important for persistent but not transient expression of CCR4 in human CD4+ T cells

Although regulation of CXCR3 and CCR4 is related to Th1 and Th2 differentiation, respectively, many CXCR3⁺ and CCR4⁺ cells do not express IFN‐γ and/or IL‐4, suggesting that the chemokine receptor genes might be inducible by mechanisms that are lineage‐independent. We investigated the regulation of CXCR3 versus IFNG, and CCR4 versus IL4 in human CD4⁺ T cells by analyzing modifications of histone H3. In naïve cord‐blood cells, under nonpolarizing conditions not inducing IL4, CCR4 was induced to high levels without many of the activation‐associated changes in promoter histone H3 found for both IL4 and CCR4 in Th2 cells. Importantly, CCR4 expression was stable in Th2 cells, but fell in nonpolarized cells after the cells were rested; this decline could be reversed by increasing histone acetylation using sodium butyrate. Patterns of histone H3 modifications in CXCR3⁺CCR4^? and CXCR3^?CCR4⁺ CD4⁺ T‐cell subsets from adult blood matched those in cells cultured under polarizing conditions in vitro. Our data show that high‐level lineage‐independent induction of CCR4 can occur following T‐cell activation without accessibility‐associated changes in histone H3, but that without such changes expression is transient rather than persistent.