Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets

Inflammatory bowel disease reflects an aberrant mucosal CD4+ T cell response to commensal enteric bacteria. In addition to regulatory T cell subsets, recent studies have revealed a protective role of B cells in murine CD4+ T cell colitis, but the relationship of their action to T cell immunoregulation is unknown. Here we report that mesenteric lymph node (MLN) B cells protect mice from colitis induced by Galphai2-/- CD4+ T cells. Protection required the transfer of both B cells and CD8alpha+ T cells; neither cell type alone was sufficient to inhibit CD4+ T cell-mediated colitis. Similar results were also observed in colitis induced by CD4+CD45RBhi T cells. Immunoregulation was associated with localization of B cells and expansion of CD4-CD8- CD3+NK1.1+ T cells in the secondary lymphoid compartment, as well as expansion of CD4+CD8alpha+ T cells in the intestinal intraepithelial compartment. MLN B cells from Galphai2-/- mice were deficient in a phenotypic subset and failed to provide cotransfer colitis protection. These findings indicate that protective action of B cells is a selective trait of MLN B cells acquired through a Galphai2-dependent developmental process and link B cells with the formation of regulatory T cells associated with mucosal immune homeostasis.     

Culture and properties of adipose-derived mesenchymal stem cells: characteristics in vitro and immunosuppression in vivo

Objective: To compare the two sources of adipose and bone marrow derived mesenchymal stem cells (BMSCs and AMSCs) in immune regulation and to evaluate the therapeutic effects of AMSCs on Con A induced hepatitis and the possible mechanism involved in it. Methods: We isolated bone marrow and adipose derived mesenchymal stem cells respectively and compared their differences on T lymphocyte activation, proliferation and suppression. We also test the anti-apoptosis ability of AMSCs on LO2 cell line. The effects of intravenous infusion of AMSCs on liver damage were also tested and we detected donor AMSCs in liver of recipient and their effects on the activity of intrahepatic NKT cells. Results: BMSCs and AMSCs were similar in cell phenotype and the difference existed only in the expression of CD106. The results showed that the capacity of suppressing T cells proliferation and activation was weakened in AMSCs. AMSCs ameliorated liver damage and this effect was time and dose dependent. We detected donor AMSCs in liver of recipient which suggested tissue damage could be a clue for AMSCs migration. We also found AMSCs suppress the activity of intrahepatic NKT cells, but this suppress effects was not restricted in liver only, but the whole body. Conclusion: Cell origin and abundance are decisive factors in stem cells applications and with the same premise of AMSCs and BMSCs, adipose tissue is a more promising origin source of stem cells. The immunoregulatory features of MSCs might play an important role in various MSCs cellular therapies.     

Prognostic Impact of Circulating CD28 Negative Suppressor T Cells and Memory B Cells on Treatment Outcomes of Patients with Breast Cancer

Background: It has been suggested that routine assessment and quantification of different lymphocyte subsets can provide clinically meaningful prognostic information in breast cancer (BC). Objective: To determine the relationship between peripheral blood lymphocyte subsets and pathological parameters and response to therapy in patients with BC. Methods: Thirty patients with operable breast cancer treated surgically with either modified radical mastectomy or breast conservative surgery, and 20 healthy controls were included. For detection of lymphocyte subsets in peripheral blood; Fluorochrome-labeled monoclonal antibodies were used and cells were analyzed by flow cytometry. Patients were treated with chemotherapy, radiotherapy and hormonal treatment, and followed up to determine relapse and recurrence-free survival (RFS). Results: Significant differences were found in the frequencies of B, T, NK, NKT, and CD28‒T cells between patients with BC and controls. Moreover, a significant difference was found in the percentage of CD8+CD28‒ T cells between patients with different pathologic subtypes of BC and negative correlations were observed between the frequency of CD8+CD28‒T cells and memory B cells, and RFS. Also, a significant difference in the frequency of naïve B cells was found in patients with different tumor grades and a negative correlation was found between the frequencies of B cells and NKT cells. Conclusion: NK, NKT, lymphocytes, and CD28‒ T cells significantly differed between healthy controls and BC patients. Also, memory B cells were associated with good response to treatment while CD28‒ T cells were associated with shorter RFS.     

肺结核患者T辅助细胞NKT细胞水平与疾病发展的关系研究

目的 探讨肺结核患者T辅助细胞、NKT细胞水平与疾病发展的关系。方法 采用流式细胞仪对陕西省榆林市星元医院2012～2014年收治的129例肺结核患者（初治肺结核患者85例,复治肺结核患者44例）与30名健康志愿者的外周血中T辅助细胞、NKT细胞的表达率进行检测。初治患者接受治疗1年后,比较分析T辅助细胞、NKT细胞水平。结果 初治肺结核患者Th2细胞含量显著高于健康志愿者（P<0.05）,Th1细胞则显著低于健康志愿者（P<0.05）。复治肺结核患者体内T辅助细胞的表达量显著高于初治肺结核患者（P<0.05）;而初治、复治肺结核患者的NKT细胞表达水平差异无统计学意义（P>0.05）。T辅助细胞在不同程度初治肺结核患者中表达率不同,差异有统计学意义（P<0.05）,患者病情越重,T辅助细胞表达率越高。不同程度初治肺结核患者的NKT细胞表达水平差异无统计学意义（P>0.05）。患者治疗后的T辅助细胞与NKT细胞表达水平与治疗前相比,差异有统计学意义（P<0.05）。结论 NKT细胞可以有助于肺结核疾病的判断,但对于不同类型及严重程度的结核病判断需要T辅助细胞的检测。     

Cancer immunoediting from immune surveillance to immune escape

Cancer immune surveillance is considered to be an important host protection process to inhibit carcinogenesis and to maintain cellular homeostasis. In the interaction of host and tumour cells, three essential phases have been proposed: elimination, equilibrium and escape, which are designated the 'three E's'. Several immune effector cells and secreted cytokines play a critical role in pursuing each process. Nascent transformed cells can initially be eliminated by an innate immune response such as by natural killer cells. During tumour progression, even though an adaptive immune response can be provoked by antigen-specific T cells, immune selection produces tumour cell variants that lose major histocompatibility complex class I and II antigens and decreases amounts of tumour antigens in the equilibrium phase. Furthermore, tumour-derived soluble factors facilitate the escape from immune attack, allowing progression and metastasis. In this review, the central roles of effector cells and cytokines in tumour immunity, and the escape mechanisms of tumour cells during tumour progression are discussed.     

Modulation of Valpha19 NKT cell immune responses by alpha-mannosyl ceramide derivatives consisting of a series of modified sphingosines

We have demonstrated that analogues of alpha-mannosyl ceramide (alpha-ManCer) consisting of a series of immunosuppressive 2-aminoalcohol derivatives in place of sphingosine promote a greater immune response from mouse invariant Valpha19-Jalpha26 (AV19-AJ33) TCR-bearing NKT (Valpha19 NKT) cells than alpha-ManCer itself. To further characterize the immune responses of Valpha19 NKT cells to the alpha-ManCer analogues, cytokine production by the cells was examined in detail. We found that certain alpha-ManCer derivatives individually induced either Th1- or Th2-dominant cytokine production in culture. The Th1- or Th2-biased immune responses of Valpha19 NKT cells were dependent on MHC class I-like MR1, since they were induced by coculture with the MR1 transfectants previously loaded with the glycolipids and were inhibited in the presence of anti-MR1 antiserum. Presumably, the recognition of the alpha-mannosyl residue of the alpha-ManCer analogues by the invariant TCR is individually modulated, depending on the altered interaction with the groove of the antigen-presenting MR1. Priming of the Valpha19 invariant TCR-transgenic mice in vivo with these glycolipid derivatives resulted in the induction of the Th1- or Th2-biased immune responses. Thus, these alpha-ManCer derivatives are likely to be useful in immunotherapy for either Th1 or Th2 excess autoimmune diseases, modulating the function of Valpha19 NKT cells.     

Immunoregulatory role of Jalpha281 T cells in aged mice developing lupus-like nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the emergence of autoreactive T cells. Humans and mice with SLE have reduced numbers of CD1d-restricted invariant natural killer T (iNKT) cells, suggesting a key role for these cells in its immunopathogenesis. This subset uses an invariant TCR constituted by Valpha14 Jalpha281 chains paired with some Vbeta domains. The regulatory role for iNKT cells in non-autoimmune mice was suggested by our previous results showing that aged Jalpha281 knockout (KO) mice produce anti-dsDNA. Here we show that old Jalpha281 KO mice have proteinuria and antibodies against dsDNA and cardiolipin. Histological analysis of Jalpha281 KO mice revealed glomeruli damage and deposition of C3c and IgG, mainly of the IgG3 subclass. In spleens of aged Jalpha281 KO mice there is an increase of activated marginal zone B cells. The evolution of lesions may depend on the age-associated increase of autoantibodies production, preferentially IgG3, mainly secreted by marginal zone B cells. Our results provide the first evidence of a lupus-like syndrome in non-autoimmune mice, supporting an age-related immunoregulatory role of Jalpha281+ cells, probably associated with the activation of marginal zone B cells.     

系统性红斑狼疮患者外周血CD3+CD56+NKT水平与Th1/Th2细胞表达的相关性

目的 探讨系统性红斑狼疮（SLE）患者外周血CD3+CD56+NKT水平与相关机制的关系。方法 选取2019年8月～2020年12月重庆市九龙坡区中医院收治的112例SLE患者（SLE组）,按SLEDAI评分分为非活动期72例,活动期40例,另选取同期健康自愿者50例（健康组）。采集受试者血采用流式细胞技术测定CD3+CD56+NKT水平,采用酶联免疫法测定血清中相关细胞因子,分析各指标与病情的相关性。结果 SLE组外周血CD3+CD56+NKT细胞计数及占比均较健康组明显减小,差异有统计学意义（P＜0.05）;SLE活动期组外周血CD3+CD56+NKT细胞计数及占比、IFN-γ、IFN-γ/IL-4明显低于非活动期组,SLEDAI评分、24 h UPQ、IL-4明显高于非活动期组,差异有统计学意义（均P＜0.05）;Pearson相关分析结果显示,CD3+CD56+NKT细胞与SLE患者SLEDAI评分、24 hUPQ及IL-4呈负相关（r=-0.573、-0.682、-0.374,P＜0.05）,而与IFN-γ无显著相关性（r=0.016,P＞0.05）。结论 CD3+CD56+NKT细胞参与了SLE免疫调节过程,其表达水平与患者SLEDAI评分呈显著负相关,CD3+CD56+NKT细胞可能通过分泌Th1/Th2细胞相关因子发挥SLE免疫调节作用,值得临床借鉴。     

Liver‐infiltrating CD56 positive T lymphocytes in hepatitis C virus infection

Abstract: Aim: Hepatitis C virus (HCV) is a major cause of post‐transfusional and sporadic hepatitis, and leads to chronic liver disease. It has been suggested that virus‐specific cytotoxic T lymphocytes are responsible for liver injuries that occur in HCV‐infected patients. However, the detailed characteristics of these lymphocytes have not yet been defined. We have previously reported that CD56⁺ T lymphocytes, as intermediates between natural killer cell and T lymphocytes, predominantly infiltrated the liver and were increased in patients with chronic hepatitis related to HCV (CH‐C). Material and Methods: We obtained peripheral blood and liver tissues from 32 patients diagnosed as having CH‐C, and 10 other liver disease patients (5 chronic hepatitis related to HBV, 5 alcoholics), and analyzed peripheral blood and liver‐infiltrating lymphocytes using flow cytometric and immunohistochemical techniques. Results: The CD56⁺ T lymphocyte ratio in the liver of patients with a high histology activity index (HAI) score for chronic hepatitis was higher than that of patients with a low HAI score and patients with other liver diseases. In addition, T lymphocytes from patients with chronic hepatitis with a high HAI score carried mostly γδ‐TCR. There was a correlation between the ratio of CH‐C and serum alanine aminotransferase, category I (periportal inflammation and necrosis), and IV (fibrosis) of the HAI scoring system. The ratio was highest in zone 1 of the hepatic lobules. Conclusion: The correlation between CD56⁺ T lymphocyte ratios and hepatocellular damage was examined. These findings suggest strongly that liver‐infiltrating CD56⁺ T lymphocytes play an important pathologic role in hepatocellular injury in CH‐C.