美沙拉嗪对DSS诱导小鼠溃疡性结肠炎模型Th1、Th17及Treg细胞亚群的影响

 目的:观察葡聚糖硫酸钠（DSS）诱导小鼠溃疡性结肠炎（UC）模型中辅助性T细胞（Th1、Th17亚群）及调节性T细胞（Treg）细胞亚群的变化,探讨美沙拉嗪（MSLZ）治疗UC的免疫学机制。方法: 采用流式细胞分析术检测DSS诱导的小鼠UC模型结肠组织及外周血单个核细胞中白细胞介素17（IL-17）、γ-干扰素（IFN-γ）及核转录因子Foxp3的表达,并检测MSLZ预治疗对小鼠UC 模型Th1、Th17和Treg亚群的影响。结果: 在DSS诱导的小鼠UC模型中,其外周血单个核细胞（PBMC）中CD3+T细胞高表达IL-17、IFN-γ及Foxp3,肠黏膜单个核细胞（LPMC）中CD3+T细胞高表达IFN-γ和Foxp3,但IL-17的表达与对照组无差异。进一步发现UC模型小鼠LPMC中Th17、Th1和Treg均显著高于对照组,但PBMC中只有Treg高于对照组。MSLZ预治疗能显著下调UC 模型小鼠PBMC和LPMC中Th17、Th1和Treg细胞亚群。结论: DSS诱导的小鼠 UC模型中CD4+T细胞亚群Th1、Th17及Treg细胞显著升高,提示CD4+T细胞亚群在UC发病中起重要作用,美沙拉嗪可能通过调节Th1、Th17及Treg细胞亚群发挥抗炎及治疗UC作用。     

Localization of IL-17+Foxp3+ T Cells in Esophageal Cancer

The etiology of cancer is unclear. Recent studies indicate that some cytokines, such as interleukin (IL)-17, and regulatory T cells are involved in the development of cancer. This study aims to detect a subset of T cell, IL17+Foxp3+ T cell, in the pathogenesis of esophageal cancer (Eca). Twelve patients with squamous Eca were recruited in this study. The surgically removed Eca tissue was collected. Cells isolated from Eca tissue were analyzed by flow cytometry. The results showed that 2–10% Eca tissue-derived CD4⁺ T cells expressed Foxp3; only 0.2–0.8% non-ca tissue-derived CD4⁺ T cells expressed Foxp3. Further analysis showed that 3–15% Eca-isolated CD4⁺ T cells were also IL-17 positive whereas only 0.4–1.5% non-ca tissue-isolated CD4⁺ T cells were IL-17 positive. We also found that about 4.8–11.2% Foxp3⁺ IL-17⁺ T cells in isolated CD4⁺ T cells from Eca tissue that were significantly less than in non-ca tissue derived CD4⁺ T cells. Less than 1% Foxp3⁺ IL-17⁺ T cells in isolated CD4⁺ T cells in both Eca patients and healthy controls. Treatment with hypoxia markedly increased the expression of IL-6 in peripheral CD68+ cells. Coculturing CD68+ cells and Foxp3+ T cells under hypoxic environment resulted in abundant expression of IL-17 in Foxp3+ T cells that could be blocked by pretreatment with either anti-IL-17 or anti-transforming growth factor beta antibodies. We conclude that IL-17+Foxp3+ T cells may contribute to the development of Eca.     

Infiltration of IL-17-Producing T Cells and Treg Cells in a Mouse Model of Smoke-Induced Emphysema

Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease associated with the accumulation of activated T cells. To date, there is little information concerning the intrinsic association among Th17, Tc17, and regulatory T (Treg) cells in COPD. The objective of this study was to investigate the variation of lungs CD4⁺Foxp3⁺ Treg cells and IL-17-producing CD4 and CD8 (Th17 and Tc17) lymphocytes in mice with cigarette-induced emphysema. Groups of mice were exposed to cigarette smoke or room air. At weeks 12 and 24, mice were sacrificed to observe histological changes by HE stain. The frequencies of Th17 (CD4⁺IL-17⁺T), Tc17 (CD8⁺IL-17⁺T), and Treg (CD4⁺Foxp3⁺T) cells in lungs from these mice were analyzed by flow cytometry. The mRNA levels of orphan nuclear receptor ROR γt and Foxp3 were performed by real-time quantitative polymerase chain reaction. The protein levels of interleukin-17 (IL-17), IL-6, IL-10, and transforming growth factor-beta (TGF-β1) were measured by enzyme-linked immunosorbent assay. Cigarette smoke caused substantial enlargement of the air spaces accompanied by the destruction of the normal alveolar architecture and led to emphysema. The frequencies of Th17 and Tc17 cells, as well as the expressions of IL-6, IL-17, TGF-β1, and ROR γt were greater in the lungs of cigarette smoke (CS)-exposed mice, particularly in the 24-week CS-exposed mice. The frequencies of Treg cells and the expressions of IL-10 and Foxp3 were lower in CS-exposed mice compared to control group. More important, the frequencies of Tregs were negatively correlated with Th17 cells and with Tc17 cells. Interestingly, a significant portion of the cells that infiltrate the lungs was skewed towards a Tc17 phenotype. Our findings suggest the contribution of Th17, Tc17, and Treg cells in the pathogenesis of COPD. Rebalance of these cells will be helpful for developing and refining the new immunological therapies for COPD.     

Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner

Galectin-9 (Gal-9) ameliorates autoimmune reactions by suppressing Th17 cells while augmenting Foxp3⁺ regulatory T cells (Tregs). However, the exact mechanism of Gal-9-mediated immune modulation has been elusive. In a MOG-induced experimental allergic encephalomyelitis model using Gal-9^−/− mice, we observed exacerbated inflammation and an increase in IL-17-producing Th17 cells balanced by a decrease in Foxp3+ Tregs. During in vitro Th17 skewing using TGF-β1 and IL-6, exogenous Gal-9 suppressed Th17 cell development and expanded Foxp3⁺ Tregs from naïve CD4 T cells in an IL-2-dependent manner. Although Gal-9 induced cell death in Tim3-expressing differentiated Th17 cells, Gal-9 suppressed Th17 development in a Tim-3-independent. Benzyl-α-GalNAc (an O-glycan biosynthesis inhibitor), but not swainsonine (a complex-type N-glycan biosynthesis inhibitor) abrogated Gal-9-mediated inhibition of Th17 development indicating that there is a linkage between Gal-9 and an unidentified glycoprotein(s) with O-linked β-galactosides that suppress Th17 development.     

Composition and plasticity of triple-negative breast carcinoma-infiltrating regulatory T cells

Low Foxp3⁺ regulatory T-cell (Treg) presence in the tumor-infiltrating lymphocytes (TILs) is considered favorable in breast cancer, and numerous CD25-targeting agents have been applied in the attempt to remove Foxp3⁺ Treg cells, which typically present CD4⁺CD25^+/hi surface phenotype. However, CD25 is not Treg-exclusive and can be upregulated by effector T cells. Hence, CD25 depletion may cause the elimination of activated T cells that are responding to tumor-specific antigens. In this study, the composition and function of CD4⁺CD25⁺ cells inside the microenvironment of triple-negative breast carcinoma (TNBC) were investigated. Directly ex vivo, the Foxp3⁺ Treg cells represented a minor subset in total CD4⁺CD25⁺ TILs. Significant differences were observed in the expression of Treg-associated molecules between CD4⁺CD25⁺Foxp3⁺ TILs and CD4⁺CD25⁺Foxp3⁻ TILs. While both the CD4⁺CD25⁺Foxp3⁺ and the CD4⁺CD25⁺Foxp3⁻ TILs could express CTLA-4 and LAG-3, the expression levels were significantly higher in CD4⁺CD25⁺Foxp3⁺ TILs than in CD4⁺CD25⁺Foxp3⁻ TILs. Upon TCR stimulation, the expression of TGF-beta was significantly higher in CD4⁺CD25⁺Foxp3⁺ TILs, while the expression of IL-10 was significantly higher in CD4⁺CD25⁺Foxp3⁻ TILs. These differences were conserved in the blood counterparts of these cells. Interestingly, the level of CD25⁺Foxp3⁺ cells in circulating CD4⁺ T cells was positively correlated with the level of CD25⁺Foxp3⁺ cells in CD4⁺ TILs, but the level of CD25⁺Foxp3⁻ cells in circulating CD4⁺ T cells was not associated with the level of CD25⁺Foxp3^- cells in CD4⁺ TILs. Th17-polarizing medium could readily remodel CD4⁺CD25⁺Foxp3⁻, but not CD4⁺CD25⁺Foxp3⁺, T cells into RORgammat and IL-17-expressing T cells, demonstrating stronger plasticity of the former subset. Together, these data demonstrated that the CD4⁺CD25⁺ TILs were composed of distinctive Foxp3⁻ and Foxp3⁺ cells, with the former representing the major subset. The antigen specificity and effector molecule expression of the CD4⁺CD25⁺Foxp3⁻ thus require further analyses.     

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.     

Macrophage Subset Expressing CD169 in Peritoneal Cavity-Regulated Mucosal Inflammation Together with Lower Levels of CCL22

Crohn’s disease (CD) and ulcerative colitis (UC) are the most widely known types of inflammatory bowel diseases (IBD) and have been paid more attention due to their increasing incidence and a substantial increase in the risk of colorectal cancer (CRC). However, the phenotype and, more importantly, the function in the regulation of mucosal inflammation by different macrophages are poorly understood, even though macrophages constitute a major subset of intestinal myeloid cells. The results firstly showed that the subset of peritoneal CD11b⁺CD169⁺ macrophages increased and CCL22 expression level decreased significantly during the DSS-induced colitis. DSS-induced colitis was alleviated in CD169-DTR mice at least partially due to the deletion CD169⁺ macrophages. Moreover, the CCL22 expression level in peritoneal macrophages from CD169-DTR mice was much higher than that from WT mice with DSS-induced colitis. And, the cell-sorting result revealed that CD11b⁺CD169⁺ macrophage cells did not express CCL22 dominantly. Further experiment in vivo demonstrated that treatment with recombinant murine CCL22 (rmCCL22) ameliorated the clinical symptoms of DSS-induced colitis. All these data indicated that macrophage subset of CD11b⁺CD169⁺ from peritoneal cavity played critical role probably together with low levels of CCL22 in DSS-induced colitis.     

Imbalance of Different Types of CD4+Foxp3+ T cells in renal transplant recipients

Aims: To determine the number of CD4⁺CD25^-Foxp3⁺, CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells in renal transplant recipients that are transplanted stable (TS), or experiencing accelerated rejection (ALR), or acute rejection (AR).

Methods: Renal transplantation was conducted in 28 patients with end-stage renal failure (ESRF). The number of peripheral CD4⁺CD25^-Foxp3⁺, CD4⁺CD25⁺Foxp3⁺, or CD4⁺CXCR5⁺Foxp3⁺ T cells and the serum levels of interleukin-10 (IL-10) were measured in pre- and post-transplant patients and these results were compared to 10 healthy controls (HC). Correlation between CD4⁺CD25⁺Foxp3⁺ and estimated glomerular filtration rate (eGFR), CD4⁺CD25^-Foxp3⁺ and serum creatinine (Cr) levels, or Cr and IL-10 levels in TS patients was also determined.

Results: The number of CD4⁺CD25^-Foxp3⁺ T cells was significantly increased in patients with ESRF, as compared to HC. Stratification analysis demonstrated that TS patients contained greater numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells, higher levels of serum IL-10, and fewer numbers of CD4⁺CD25^-Foxp3⁺ T cells than ESRF patients. In contrast, ALR and AR patients contained fewer numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells, greater numbers of CD4⁺CD25^-Foxp3⁺ T cells, and lower levels of serum IL-10 than ESRF patients. In TS patients, the numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^-Foxp3⁺ T cells were positively correlated with eGFR and serum Cr levels, respectively.

Conclusion: An imbalance of different types of CD4⁺Foxp3⁺ T cells might be involved in renal transplant rejection.     

Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells

In both humans and animal models, the development of Sjögren syndrome (SS) and non-SS keratoconjunctivitis sicca (KCS) increases with age. Here, we investigated the ocular surface and lacrimal gland (LG) phenotype of NOD.B10.H2^b mice at 7–14, 45–50, and 96–100 weeks. Aged mice develop increased corneal permeability, CD4⁺ T-cell infiltration, and conjunctival goblet cell loss. Aged mice have LG atrophy with increased lymphocyte infiltration and inflammatory cytokine levels. An increase in the frequency of CD4⁺Foxp3⁺ T regulatory cells (Tregs) was observed with age in the cervical lymph node (CLN), spleen, and LG. These CD4⁺CD25⁺ cells lose suppressive ability, while maintaining expression of Foxp3 (forkhead box P3) and producing interleukin-17 (IL-17) and interferon-γ (IFN-γ). An increase of Foxp3⁺IL-17⁺ or Foxp3⁺IFN-γ⁺ cells was observed in the LG and LG-draining CLN. In adoptive transfer experiments, recipients of either purified Tregs or purified T effector cells from aged donors developed lacrimal keratoconjunctivitis, whereas recipients of young Tregs or young T effector cells failed to develop disease. Overall, these results suggest inflammatory cytokine-producing CD4⁺Foxp3⁺ cells participate in the pathogenesis of age-related ocular surface disease.     

Dietary gluten alters the balance of pro‐inflammatory and anti‐inflammatory cytokines in T cells of BALB/c mice

Several studies have documented that dietary modifications influence the development of type 1 diabetes. However, little is known about the interplay of dietary components and the penetration of diabetes incidence. In this study we tested if wheat gluten is able to induce differences in the cytokine pattern of Foxp3⁺ regulatory T cells, as well as Foxp3⁻ T cells, isolated from intestinal mucosal lymphoid tissue and non-mucosal lymphoid compartments in BALB/c mice. The gluten-containing standard diet markedly changed the cytokine expression within Foxp3⁻ T cells, in all lymphoid organs tested, towards a higher expression of pro-inflammatory interferon-γ (IFN-γ), interleukin-17 (IL-17) and IL-2. In Foxp3⁺ regulatory T cells, gluten ingestion resulted in a mucosal increase in IL-17 and IL-2 and an overall increase in IFN-γ and IL-4. The gluten-free diet induced an anti-inflammatory cytokine profile with higher proportion of transforming growth factor-β (TGF-β)⁺ Foxp3⁻ T cells in all tested lymphoid tissues and higher IL-10 expression within non-T cells in spleen, and a tendency towards a mucosal increase in TGF-β⁺ Foxp3⁺ regulatory T cells. Our data shows that the gluten-containing standard diet modifies the cytokine pattern of both Foxp3⁻ T cells and Foxp3⁺ regulatory T cells towards a more inflammatory cytokine profile. This immune profile may contribute to the higher type 1 diabetes incidence associated with gluten intake.     

Exogenous interleukin‐33 targets myeloid‐derived suppressor cells and generates periphery‐induced Foxp3+ regulatory T cells in skin‐transplanted mice

Interleukin-33 (IL-33) has been a focus of study because of its variety of functions shaping CD4⁺ T-cell biology. In the present work, we evaluated the modulatory effect of IL-33 on suppressor cells in an in vivo transplantation model. C57BL/6 wild-type mice were grafted with syngeneic or allogeneic skin transplants and treated with exogenous IL-33 daily. After 10 days of treatment, we analysed draining lymph node cellularity and found in allogeneic animals an increment in myeloid-derived suppressor cells, which co-express MHC-II, and become enriched upon IL-33 treatment. In line with this observation, inducible nitric oxide synthase and arginase 1 expression were also increased in allogeneic animals upon IL-33 administration. In addition, IL-33 treatment up-regulated the number of Foxp3⁺ regulatory T (Treg) cells in the allogeneic group, complementing the healthier integrity of the allografts and the increased allograft survival. Moreover, we demonstrate that IL-33 promotes CD4⁺ T-cell expansion and conversion of CD4⁺ Foxp3⁻ T cells into CD4⁺ Foxp3⁺ Treg cells in the periphery. Lastly, the cytokine pattern of ex vivo-stimulated draining lymph nodes indicates that IL-33 dampens interferon-γ and IL-17 production, stimulating IL-10 secretion. Altogether, our work complements previous studies on the immune-modulatory activity of IL-33, showing that this cytokine affects myeloid-derived suppressor cells at the cell number and gene expression levels. More importantly, our research demonstrates for the first time that IL-33 allows for in vivo Foxp3⁺ Treg cell conversion and favours an anti-inflammatory or tolerogenic state by skewing cytokine production. Therefore, our data suggest a potential use of IL-33 to prevent allograft rejection, bringing new therapeutics to the transplantation field.     

Altered generation of induced regulatory T cells in the FVB.mdr1a−/− mouse model of colitis

The FVB.mdr1a^−/− mouse, lacking the small molecule pump P-glycoprotein (P-gp), is a commonly used model for the study of spontaneous T cell–mediated colitis. In addition, MDR1 polymorphisms and P-gp deficiency in humans have been linked to the development of ulcerative colitis. We now demonstrate that mice with P-gp deficiency have decreased levels of Foxp3⁺ regulatory T cells (Tregs) in the intestinal lamina propria. This decrease is not due to either increased Treg apoptosis, altered Treg trafficking, or enhanced Treg plasticity to become Foxp3⁺IL-17⁺ cells. Instead, P-gp deficiency appears to restrict the development of induced Treg cells (iTregs), as fewer Foxp3⁺ iTregs developed from naive FVB.mdr1a^−/− T cells both upon transforming growth factor-β (TGF-β) treatment in vitro and after adoptive transfer into FVB.rag2^−/− recipients. Rather, in vitro TGF-β treatment results in a IL-17⁺CD4⁺ T cell. This failure of iTregs to develop explains the decrease in Foxp3⁺ Tregs in the FVB.mdr1a^−/− intestine, representing a need to investigate this novel disease mechanism in human inflammatory bowel disease patients with MDR1 polymorphisms.     

Host-dependent control of early regulatory and effector T-cell differentiation underlies the genetic susceptibility of RAG2-deficient mouse strains to transfer colitis

De novo differentiation of CD4⁺Foxp3⁺ regulatory T cells (induced (i) Tregs) occurs preferentially in the gut-associated lymphoid tissues (GALT). We addressed the contribution of background genetic factors in affecting the balance of iTreg, T helper type 1 (Th1), and Th17 cell differentiation in GALT in vivo following the transfer of naive CD4⁺CD45RB^high T cells to strains of RAG2-deficient mice with differential susceptibility to inflammatory colitis. iTregs represented up to 5% of CD4⁺ T cells in mesenteric lymph nodes of less-susceptible C57BL/6 RAG2^−/− mice compared with <1% in highly susceptible C57BL/10 RAG2^−/− mice 2 weeks following T-cell transfer before the onset of colitis. Early Treg induction was correlated inversely with effector cell expansion and the severity of colitis development, was controlled primarily by host and not T-cell-dependent factors, and was strongly associated with interleukin-12 (IL-12)/23 production by host CD11c⁺CD103⁺ dendritic cells. These data highlight the importance of genetic factors regulating IL-12/23 production in controlling the balance between iTreg differentiation and effector-pathogenic CD4⁺ T-cell expansion in lymphopenic mice and indicate a direct role for iTregs in the regulation of colonic inflammation in vivo.     

Dendritic cells produce TSLP that limits the differentiation of Th17 cells, fosters Treg development, and protects against colitis

Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and keratinocytes, and is involved in immune homeostasis or inflammation. The mechanism through which TSLP regulates intestinal inflammation is unclear. Here, we report that mouse dendritic cells (DCs) express TSLP both in vitro and in vivo in response to Toll-like receptor ligation in a MyD88-dependent fashion. TSLP is produced by the CD103+ subset of tolerogenic gut DCs and is downregulated during experimental colitis. TSLP produced by DCs acts directly on T cells by reducing their capacity to produce interleukin (IL)-17 and fostering the development of Foxp3⁺+ T cells. Consistently, TSLP protects against colitis development through a direct action on T cells, as adoptive transfer of naïve T cells from TSLPR^−/− to SCID mice results in a more severe colitis, with increased frequency of IL-17-producing T cells and inflammatory cytokines. Hence, we describe a new anti-inflammatory role of TSLP in the gut.     

Anti-CD8 treatment reduces the severity of inflammatory arthritis, but not vasculitis, in mercuric chloride-induced autoimmunity

T cell hypersensitivity has been implicated in the tissue damage in Crohn's disease (CD). All studies to date have examined mucosal T cells, although much of the tissue damage occurs in the submucosa and muscle layers. The aim of this work was to study T cell proliferation throughout the intestinal wall in children with IBD. Surgical resection material from 19 children with CD (10 ileal, 10 colonic), seven with ulcerative colitis (UC), and 12 normal controls was studied. The distribution of dividing T cells was investigated by double-immunohistochemistry using Ki67 to identify proliferating cells, and CD3 to identify T cells. In ileal and colonic lamina propria virtually no Ki67⁺, CD3⁺ cells were seen in control, UC or CD tissue. In contrast, there were significantly more Ki67⁺, CD3⁺ cells within the lymphoid follicles of ileal and colonic CD than in the follicles in UC and controls. Increased numbers of Ki67⁺, CD3⁺ cells were present in the submucosa, muscle layers (M) and serosa in Crohn's ileitis and colitis compared with the lamina propria (LP), although only in the muscle of the colon was the difference statistically significant (LP, 0.4% (0–1%); M, 1.6% (0–5.2%); P = 0.03). Pooling data from ileal and colonic CD, however, did show significantly increased Ki67⁺, CD3⁺ cells in both serosa and muscle layers compared with the LP. Dividing T cells have been identified in the deeper layers of the gut wall in CD. These may contribute to the fibrosis and muscle hyperplasia characteristic of the condition.     

Vaccinated C57BL/6 Mice Develop Protective and Memory T Cell Responses to Coccidioides posadasii Infection in the Absence of Interleukin-10

High concentrations of lung tissue-associated interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, correlate with susceptibility of mice to Coccidioides spp. infection. In this study, we found that macrophages, dendritic cells, neutrophils, and both CD8⁺ and CD4⁺ T cells recruited to Coccidioides posadasii-infected lungs of nonvaccinated and vaccinated mice contributed to the production of IL-10. The major IL-10-producing leukocytes were CD8⁺ T cells, neutrophils, and macrophages in lungs of nonvaccinated mice, while both Foxp3⁺ and Foxp3⁻ subsets of IL-10⁺ CD4⁺ T cells were significantly elevated in vaccinated mice. Profiles of the recruited leukocytes in lungs revealed that only CD4⁺ T cells were significantly increased in IL-10^−/− knockout mice compared to their wild-type counterparts. Furthermore, ex vivo recall assays showed that CD4⁺ T cells isolated from vaccinated IL-10^−/− mice compared to vaccinated wild-type mice produced significantly higher amounts of IL-2, gamma interferon (IFN-γ), IL-4, IL-6, and IL-17A in the presence of a coccidioidal antigen, indicating that IL-10 suppresses Th1, Th2, and Th17 immunity to Coccidioides infection. Analysis of absolute numbers of CD44⁺ CD62L⁻ CD4⁺ T effector memory T cells (T_EM) and IFN-γ- and IL-17A-producing CD4⁺ T cells in the lungs of Coccidioides-infected mice correlated with better fungal clearance in nonvaccinated IL-10^−/− mice than in nonvaccinated wild-type mice. Our results suggest that IL-10 suppresses CD4⁺ T-cell immunity in nonvaccinated mice during Coccidioides infection but does not impede the development of a memory response nor exacerbate immunopathology of vaccinated mice over at least a 4-month period after the last immunization.     

Mannose-capped lipoarabinomannan-induced B10 cells decrease severity of dextran sodium sulphate-induced inflammatory bowel disease in mice

Inflammatory bowel disease (IBD) is a chronic, non-specific, inflammatory gastrointestinal disease that mainly consists of Crohn's disease and ulcerative colitis. However, the aetiology and pathogenesis of IBD are still unclear. B10 (IL-10 producing regulatory B) cells, a subset of regulatory B cells, are known to contribute to intestinal homeostasis and the aberrant frequency of B10 cells is associated with IBD. We have recently reported that B10 cells can be induced by ManLAM (mannose-capped lipoarabinomannan), a major cell-wall lipoglycan of M tb (Mycobacterium tuberculosis). In the current study, the ManLAM-induced B10 cells were adoptively transferred into IL(interleukin)-10^−/− mice and the roles of ManLAM-induced B10 cells were investigated in DSS (dextran sodium sulphate)-induced IBD model. ManLAM-induced B10 cells decrease colitis severity in the mice. The B10 cells downregulate Th1 polarization in spleen and MLNs (mesenteric lymph nodes) of DSS-treated mice. These results suggest that IL-10 production by ManLAM-treated B cells contributes to keeping the balance between CD4⁺ T cell subsets and protect mice from DSS-induced IBD.