阻断4-1BB/4-1BBL通路在系统性红斑狼疮患者T淋巴细胞活化中的作用

目的 探讨协同刺激分子4-1BB/4-1BBL在系统性红斑狼疮(systemic lupus erythematosus,SLE)T淋巴细胞活化中的作用机制.方法 应用RT-PCR和Western blot方法检测体外培养20例SLE患者和20例正常对照者T淋巴细胞活化前后及应用抗4-1BB单抗阻断后p38 MAPK和NF-kB表达的变化.结果 SLE患者T淋巴细胞NF-kB mRNA和p38 MAPK mRNA表达及其蛋白水平明显高于正常对照组(P均＜0.01),活化后的表达进一步升高(P均＜0.01).阻断4-1BB/4-1BBL通路后SLE患者T淋巴细胞p38 MAPK mRNA及蛋白水平的表达均明显下降(P均＜0.01),但是NF-kB mRNA及蛋白水平的表达无明显变化(P＞0.05).结论 协同刺激分子4-1BB可能通过p38MAPK信号转导通路促使SLE患者T淋巴细胞的活化与增殖.     

Viral hemagglutinin augments peptide-specific cytotoxic T cell responses

In attempt to increase the induction of peptide-specific cytolytic T cells (CTL) we investigated the effect of the Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) gene product on the activation of peptide-specific CTL. Spleen cells of CH3 mice immunized against the influenza nucleoprotein peptide 50–63 (NP 50–63) were restimulated in vitro (i) with peptide-pulsed syngeneic fibroblast cells (Ltk^?) as antigen-presenting cells, which were in addition (ii) infected with NDV or (iii) stably transfected with the HN cDN A of NDV. A greater than sixfold increase in peptide-specific CTL responses was observed in cultures restimulated with peptide-pulsed Ltk^? cells which co-expressed viral hemagglutinin due to either infection or transfection. A similar augmentation was seen in CTL responses against other types of antigen (major histocompatibility complex alloantigens, minor histocompatibility antigens or tumor antigens) when suboptimal cultures were stimulated with the respective antigen-presenting cells modified by NDV infection. These findings suggest that NDV or viral HN expressed on antigen-presenting cells or tumor cells can exert a T cell co-stimulatory function.     

Both IFN-γ and IL-4 Induce MHC Class II Expression at the Surface of Mouse Pro-B Cells

Pro-B cells are early B-cell progenitors that retain macrophage potential. We have studied MHC class II molecules and invariant chain inducibility on four class II negative mouse pro- B-cell clones. We analyzed the effects of IL-4 and IFN-γ, which represent the major inducers of class II in the B-lymphoid and monocytic/macrophage lineages, respectively. After 48 h of treatment with either cytokine, three pro-B-cell clones (C2.13, A1.5, and F2.2) expressed intracellular invariant chain and cell-surface class II molecules. One clone (D2.1) remained negative. As already reported, more differentiated 70Z/3 pre-B cells were inducible by IL-4 only. These data suggest that the induction of class II and invariant-chain genes are subject to regulation throughout B-cell differentiation.     

Rapid tyrosine phosphorylation of Grb2 and Shc in T cells exposed to anti-CD3, anti-CD4, and anti-CD45 stimuli: differential effects of aging

Two adapter proteins, Grb2 and Shc, have recently been implicated in the transmission of activation signals from the stimulated T cell receptor to Ras. We show here that in vitro stimulation of mouse splenic T cells with crosslinked anti-CD3 antibody leads within 30 s to phosphorylation of both Grb2 and Shc. Treatment with crosslinked anti-CD45 antibody leads to phosphorylation of Grb2 and also to a slight retardation in the mobility of this protein in an SDS polyacrylamide gel; both changes are seen within 30 s of crosslinking. Crosslinked anti-CD4 antibody leads to phosphorylation of Shc and to the phosphorylation of a 30-kDa protein that cross-reacts with anti-Grb2 antibodies. Aging leads to a decline in CD3-stimulated phosphorylation of Shc (but not Grb2), and to an increase in CD4-stimulated phosphorylation of Grb2, Shc, and the 30-kDa Grb2-like protein. Increased tyrosinephosphorylation of Grb2 after exposure to either anti-CD3 or anti-CD45 suggests that Grb2 may be a common substrate for both CD3-linked kinases and the CD45 phosphatase. The differences between T cells from young and old mice suggest that aging may lead to a set of alterations in kinase/substrate coupling that contribute to immune dysfunction in the elderly, and that activation of the Ras pathway might be impaired by aging in T lymphocytes.     

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

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Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells

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Functional variation of HIV-1 Rev Response Element in a longitudinally studied cohort

We showed previously that HIV-1 Rev Response Element (RRE) contains a certain degree of structural variation, and in a set of limited samples, RRE from HIV-1 natural isolates were found to have functional variability. The significance of the RRE heterogeneity is addressed further by analyzing the functional variation of RREs in a longitudinal cohort. While the RRE activity at early time points was not a good predictor of disease outcome, the RRE activity at late time points was correlated with rates of CD4+ count decline. These data suggest that RRE heterogeneity may be important in viral pathogenesis and disease progression.     

过继转输胚胎抗原耐受T细胞诱导自然流产孕鼠母胎免疫耐受

探讨过继转输胚胎抗原耐受T细胞对小鼠自然流产模型妊娠预后及宿主孕鼠免疫细胞对父系抗原免疫耐受状态的影响。以CBA/J×BALB/c为正常妊娠模型 ,CBA/J×DBA/ 2为自然流产模型 ,将自然流产模型CBA/J孕鼠于孕 4d (着床期 )分别腹腔注射大鼠抗小鼠CD80和CD86mAb或大鼠同型IgG。于孕 9d ,应用免疫磁珠阴性分选三组孕鼠的脾脏T细胞 ,并将三组T细胞分别转输至孕 4d的CBA/J×DBA/ 2孕鼠。于宿主孕鼠孕第 9天 ,采用单向混合淋巴细胞反应分析宿主孕鼠脾脏免疫细胞对父系抗原的增殖能力 ,并用流式细胞术分析经父系抗原刺激的宿主孕鼠脾脏T细胞内IL 2表达水平。于孕 1 4d分别观察宿主孕鼠的胚胎吸收率。结果显示 ,过继转输胚胎抗原耐受T细胞和转输正常妊娠模型孕鼠的T细胞均可诱导宿主孕鼠脾脏免疫细胞对父系抗原的增殖能力及IL 2的表达显著下降 (P <0 0 5 ) ,孕 1 4d胚胎吸收率也显著下降 (P <0 0 5 )。这些结果表明 ,于孕早期过继转输胚胎抗原耐受T细胞和转输正常妊娠模型孕鼠的T细胞能诱导宿主孕鼠母 胎免疫耐受 ,防止母体对胚胎的免疫排斥 ,从而使自然流产模型的妊娠预后达到正常妊娠水平。     

Phenotypic characterization of regulatory CD4+CD25+ T cells in rats

CD25 has become widely used as a marker for a subset of regulatory CD4(+) T cells present in the thymus and periphery of mice, rats and humans. However, CD25 is also expressed on conventionally activated T cells that are not regulatory and not all peripheral regulatory T cells express CD25. The identification of a stable and unique marker for regulatory T cells would therefore be valuable. This study provides a detailed account of the phenotype of CD4(+)CD25(+) regulatory T cells in rats. In the thymus, CD4(+)CD8(-)CD25(+) cells were found to have a more mature phenotype than the corresponding CD4(+)CD8(-)CD25(-) cells with respect to expression of Thy1 (CD90), CD53 and CD44, suggesting that CD25 expression, and perhaps commitment to regulatory function, might be a late event in thymocyte development. CD4(+)CD25(+) cells in both the thymus and periphery were found to have enriched and heterogeneous expression of activation markers such as OX40 (CD134) and OX48 (an antibody determined in this study to be specific for CD86). CD4(+)CD25(+) T cells were also found to have enriched expression of CD80, at both the mRNA and protein level. However, functional studies in vitro and in vivo showed that neither OX40 or CD86 were useful markers for the further subdivision of regulatory T cells. Our studies indicate that, at present, CD25 remains the most useful marker to enrich for regulatory CD4(+) T cells in rats and no further subdivision of the regulatory component of CD4(+)CD25(-)CD45RC(low) T cells has yet been achieved.     

Immunohistochemical analysis of thymidylate synthase, p16(INK4a), cyclin-dependent kinase 4 and cyclin D1 in colorectal cancers receiving preoperative chemotherapy: significance of p16(INK4a)-mediated cellular arrest as an indicator of chemosensitivity to 5-fluorouracil

High expression of thymidylate synthase (TS) is allegedly associated with the chemoresistance to 5-fluorouracil (5-FU) in colorectal cancers. However, low TS expression does not necessarily imply chemosensitivity. Inactivation of p16(INK4a) correlates with poor prognosis in various cancers. We immunohistochemically evaluated the relationship between the expression of TS, p16(INK4a), CDK4 and cyclin D1 and the effect of 5-FU-based chemotherapy in colorectal cancers. After antigen retrieval, immunoperoxidase staining was performed on the paraffin-embedded, biopsy and surgical specimens of 37 advanced colorectal cancers preoperatively treated with peroral administration of 5-FU derivatives. As a control group, 31 colorectal cancers without preoperative treatment were analyzed. High TS expression was found in 23 (74%) of 31 tumors resected from histological non-responders and in 19 (61%) of 31 controls but in none of six responders. High p16(INK4a) expression was seen in 83% of the responders, 52% of the non-responders and 32% of the controls. The TS-low/p16(INK4a)-high phenotype was noted in 83% of the responders, but only in 3% of the non-responders (P = 0.0001). Induction of p16(INK4a) expression after chemotherapy was predominantly seen in the responders. Neither CDK4 nor cyclin D1 expression was related to the chemotherapeutic effects. In conclusion, the combination of low expression of TS and induction of p16(INK4a) after chemotherapy can be important indicators of the sensitivity to 5-FU-based chemotherapy in colorectal cancers.