关键词： B7   carcinoembryonic antigen (CEA)   CTLA-4   DNA vaccination   cancer vaccine   IL-10   regulatory T cells   transforming growth factor beta   TUMOR-IMMUNITY   MECHANISMS   EXPRESSION   RESPONSES   FAMILY   B7   ANTI-CTLA-4   LYMPHOCYTES   COMBINATION   ENGAGEMENT  

摘要： We have shown that a plasmid encoding a B7-1/Ig fusion protein enhanced DNA vaccination against human carcinoembryonic antigen (CEA) more effectively than the plasmid encoding membrane-bound B7-1. However, it was not known if B7-1/lg acted only by binding CD28 (amplifying a stimulatory signal) or by blocking CTLA-4 on T cells (removing inhibitory signals). Here, we aimed to determine this using a plasmid encoding mutant B7-1/Ig (B7-1wa/Ig), which binds only to CTLA-4 but not to CD28. Our results showed that both the B7-1/Ig and B7-1wa/Ig plasmids, when co-administered with a CEA plasmid, enhanced tumor rejection and the in vitro anti-CEA response. Therefore, B7- 1wa/Ig ameliorates DNA vaccination, presumably by binding to CTLA-4. This could result from a number of non-exclusive mechanisms, such as a reduced threshold for T-cell activation, or blockade of CTLA-4/B7-mediated tolerogenic signals in DCs or T cells. We found that, in vitro, a significant fraction of CD3/CD28-activated T cells (in the absence of DCs) expressed CTLA-4 and B7- 1. Primed T cells of CTLA4(+)B7-1(+/-) phenotype acted as regulatory T cells by inhibiting IFN-gamma production by re-stimulated CTLA-4(-)B7-1(-) cells, and this was reversed by antibodies against IL-10 or TGF-beta 1. Both B7-1wa/Ig and CTLA-4/Ig, which bind to CTLA-4 and B7-1/B7-2 respectively, enhanced IFN gamma production, but not the proliferation or IL-4 release in mixed T-cell populations containing these two cell types. In contrast, CTLA-4(-)B7-1(-) T cells produced IFN gamma which was not affected by B7-1wa/Ig or CTLA-4/Ig. These results suggest that blocking of CTLA-4/B7-1 binding in T cell/T cell interactions blocks negative regulatory signals. This might be the mechanism, at least in part, of the enhancement of anti-tumor immunity by the B7-1wa/Ig and B7-1/lg plasmids. (c) 2005 Elsevier Ltd. All rights reserved.

关键词： PRIMARY IMMUNE-RESPONSE   GERMINAL CENTER   IN-VITRO   EXPRESSION   CHEMOKINE   INDUCTION   TOLERANCE   MEMORY   (4-HYDROXY-3-NITROPHENYL)ACETYL   PROLIFERATION  

摘要： How Tregs migrate to GCs, and whether they regulate the helper activity of the T cells in GCs (GC-Th cells) remains poorly understood. We found a T cell subset in human tonsils that displays potent suppressive activities toward GC-Th cell-dependent B cell responses. These Tregs with the surface phenotype of CD4(+)CD25(+)CD69(-) migrate well to CCL19, a chemokine expressed in the T cell zone, but poorly to CXCL13, a chemokine expressed in the B cell zone. This migration toward the T cell-rich zone rapidly changes to trafficking toward B cell follicles upon T cell activation. This change in chemotactic behavior upon activation of T cells is consistent with their switch in the expression of the 2 chemokine receptors CXCR5 and CCR7. CD4(+)CD25(+)CD69(-) Tregs suppress GC-Th cells and GC-Th cell-induced B cell responses such as Ig production, survival, and expression of activation-induced cytosine deaminase. Our results have identified a subset of Tregs that is physiologically relevant to GC-Th cell-dependent B cell responses and a potential regulation mechanism for the trafficking of these Tregs to GCs.

关键词： KILLER-CELLS   PERFORIN   CD4(+)   MUTATIONS   EXPANSION   GENES   GAMMA  

摘要： Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the perforin/granzyme pathway as a major mechanism to kill pathogen-containing cells and tumor cells.' 2 Dysregulation of this pathway results in several human diseases, such as hemophagocytic lymphohistiocytosis. Here we characterize the single-cell expression pattern of granzymes A and B in human lymphocytes using a flow cytometry-based assay. We demonstrate that most circulating CD56(+)8(-) NK cells, and approximately half of circulating CD8(+) T lymphocytes, coexpressed both granzymes A and B. In contrast, few circulating CD4(+) T lymphocytes expressed granzymes A or B. Activation of CD8(+) T lymphocytes with concanavalin A (ConA)/interleukin-2 (IL-2), and activation of CD4(+) T lymphocytes with antibodies to CD3/CD28 or CD3/CD46 (to generate T regulatory [Tr1] cells), induced substantial expression of granzyme B, but not granzyme A. Naive CD4(+)CD45RA(+) cells stimulated with antibodies to CD3/CD46 strongly expressed granzyme B, while CD3/CD28 stimulation was ineffective. Finally, we show that granzyme B-expressing CD4(+) TO cells are capable of killing target cells in a perforin-dependent, but major histocompatibility complex (MHC)/T-cell receptor (TCR)-independent, manner. Our results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation. (C) 2004 by The American Society of Hematology.

关键词： INFLAMMATORY-BOWEL-DISEASE   INTESTINAL INFLAMMATION   REGIONAL IMMUNITY   ADOPTIVE TRANSFER   E-CADHERIN   SCID MICE   B-1 CELLS   IN-VIVO   EXPRESSION   RECEPTOR  

摘要： SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4(+) T cells expressing the alpha(E)beta(7) integrin. Although alpha(E)beta(7)(+)CD4(+) T cells possess a regulatory phenotype (CD25(+), L-selectin(lo), and CD45RB(lo)), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4+ T cells, although the CD4(+)CD25(+) subset, which overlaps with the alpha(E)beta(7)(+)CD4(+) subset, prevents colitis. The alpha(E)beta(7)(+)CD4(+) T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA(+) cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4+ T cells increases ileitis severity in SCID mice compared with transfer of CD4+ T cells alone. SAMP1/YitFc B cells prevent alpha(E)beta(7)(+)CD4(+) T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis.

关键词： B细胞非霍奇金淋巴瘤患者   外周血   调节性   T细胞分析  

摘要： 背景及目的:目前认为B细胞非霍奇金淋巴瘤(B-NHL)常伴随免疫抑制,CD4+CD25+-Tregs细胞是一种新型免疫抑制性调节细胞,在肿瘤的免疫抑制及免疫逃逸机制中起重要作用,但它在B-NHL患者外周血的分布情况及其免疫抑制中的作用目前尚不清楚。本文通过分析它在化疗前及化疗后B-NHL患者外周血中比例及变化规律,初步探讨B-NHL的免疫抑制机制,以及化疗对免疫抑制的影响,为有效干预患者免疫功能提供参考。方法:应用流式细胞仪检测39例初治化疗前的B-NHL患者、32例经4～6周期化疗后完全缓解或部分缓解的B-NHL患者和25例健康志愿者外周静脉血中CD3+、CD4+、CD8+及CD4+CD25+CTLA4+-T细胞的比例。结果:化疗前组患者淋巴细胞总数及CD4+T细胞比例、CD4/CD8比值均低于正常对照组犤分别为(1.3±0.39)×109,(2.1±0.41)×109;(27.5±4.1)%,(32.9±5.8)%;0.9±0.21,1.31±0.4犦,但其CD4+CD25+-Tregs及CD4+CD25+CTLA4+-T细胞比例明显高于正常对照组犤分别为(14.7±3.1)%,(8.4±2.5)%;(7.4±1.6)%,(5.1±1.4)%犦。尽管化疗组CD4/CD8比值(1.19±0.3)与正常组接近,但其淋巴细胞总数犤(0.8±0.53)×109犦低于初治组和正常对照组,CD4+CD25+-Tregs比例犤(20.3±4.1)%犦及CD4+CD25+CTLA4+-T细胞比例犤(11.5±2.2)%犦则明显高于化疗前?

关键词： NF-κB诱导激酶   基因突变   CD4^+CD25^+调节性T细胞   产生   影响   自身免疫病  

摘要： 目的 :探讨NIK基因变异鼠—aly鼠自身免疫病的产生与CD4+ CD2 5 + 调节性T细胞的相关性。方法 :利用NIK基因自然突变鼠—aly aly鼠做为动物模型 ,aly +小鼠做为NIK基因正常对照鼠 ;CD4+ CD2 5 + T细胞亚群鉴定采用流式细胞分析仪 (FACS) ;用免疫组织化学方法观察胸腺结构。结果 :aly小鼠的CD4+ CD2 5 + CD8- 胸腺细胞数量和脾脏CD4+ CD2 5 + CD8- T淋巴细胞的数量明显低于aly +小鼠 ;aly小鼠胸腺髓质缺少UEA 1阳性细胞。结论 :NIK基因突变的aly小鼠CD4+ CD2 5 + 胸腺细胞和脾脏T淋巴细胞的数量明显降低可能是aly小鼠自身免疫病产生的原因 ;UEA 1阳性细胞很可能在CD4+ CD2 5 + 调节性T细胞选择中发挥作用。

关键词： PANCREATIC LYMPH-NODES   ADOPTIVE TRANSFER   ANTIBODY-RESPONSES   ANTIGEN   SUBUNIT   MOUSE   TOLERANCE   SUPPRESSION   INDUCTION   IL-4  

摘要： Restoration of peripheral tolerance to target autoantigens during autoimmune diseases has met with several limitations because of the limited efficacy of this approach in an already immune host. To optimize the induction of tolerance, we have shown that feeding insulin conjugated to cholera toxin B-subunit (CTB), a potent mucosal adjuvant, reduced by 5,000 the amounts of antigen necessary for delaying diabetes onset in NOD mice. To analyze these protective mechanisms, we have performed cotransfer experiments using splenocytes from young females fed once with 10 mu g of CTB-insulin, mixed with diabetogenic T-cells, and intravenously injected into irradiated syngeneic male recipients, We demonstrated that the delayed onset of diabetes relied on CD4(+) T-cells. We studied the cytokine production from plate-bound anti-CD3-stimulated cells. Higher interleukin (IL)-4 amounts were observed in both splenocytes and pancreatic lymph node (PLN) cell cultures from CTB-insulin-fed mice as soon as 4 h after the Feeding. An increase in the levels of transforming growth factor-beta was seen after 24 h only in the mesenteric lymph nodes (MLN). In both of these organs, a reduction of gamma-interferon (IFN-gamma) production occurred after CTB-insulin treatment, at 24 h in the PLN and at 7 days in the MLN. Reverse transcription-polymerase chain reaction analysis indicated an increase in the level of IL-4 and a reduction in IFN-gamma transcripts in the PLN of mice treated orally with CTB-insulin and of the recipients of regulatory T-cells. Using different strains of congenic NOD mice at the Thy1 locus, me showed that protection was associated with the accumulation of T-cells from CTB-insulin-fed mice in the lymph nodes Tram draining sites containing functional islets, i.e., the PLN in normal mice and the renal lymph nodes after a syngeneic islet graft under the kidney capsule of streptozotocin-treated mice. Taken together, our results clearly indicate that oral administration of CTB-ins

关键词： NOD MICE   ADOPTIVE TRANSFER   AUTOIMMUNE-DISEASES   SUPPRESSOR CELLS   LYMPH-NODES   BETA-CELLS   MOUSE   TOLERANCE   MODEL   ANERGY  

摘要： The mechanism of protection from type 1 diabetes conferred by regulatory T-cells induced by oral insulin treatment of NOD mice is not well understood. We demonstrate that oral insulin feeding of NOD mice induces the function of insulin B-chain reactive CD4(+) regulatory T-cells, which compete with diabetogenic effector T-cells for the recognition of insulin in *** recipient mice. These effector T-cells become deprived of interleukin (IL)-2 and interferon (IFN)-gamma and are unable to expand and migrate to the pancreas. Type 1 diabetes-protective splenic regulatory T-cells secrete relatively little transforming growth factor (TGF)-beta 1, suggesting that TGF-beta may not contribute to the inactivation of effector T-cells in NOD,Scid recipients. The observed preferential infiltration of insulin-reactive regulatory T-cells rather than effector T-cells in the pancreas results in a nondestructive insulitis that correlates with an increased intrapancreatic expression of macrophage inflammatory protein-1 beta. Thus, oral insulin therapy overcomes a deficiency in regulatory T-cells and protects against type 1 diabetes by inducing insulin B-chain reactive regulatory T-cells to block cytokine secretion and migration of diabetogenic effector T-cells to the pancreas. Our data emphasize that continuous oral insulin feeding over a prolonged period is required to prevent type 1 diabetes.

关键词： EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS   VERSUS-HOST DISEASE   LYMPHOCYTES-T   RECEPTOR   CLONES   MICE   VACCINATION   TOLERANCE   ANTIGEN   IDENTIFICATION  

摘要： Naive T cells mount a vigorous proliferative response to superantigen (SAg) stimulation in vivo. The proliferative response is followed by a partial deletion of responder T cells. Part of the deletion process has recently been attributed to the action of regulatory cytotoxic T cells that recognize major histocompatibility complex (MHC) class I-associated antigen receptor determinants on the target cell surface. Responder T cells that survived the SAg response were found to be incapable of generating a secondary proliferative response to a SAg challenge. We show here that this 'anergy' is enforced by CD8-positive regulatory suppressive T cells. These regulatory cells inhibit cell division of preactivated T cells but not the SAg response of naive T cells. Regulatory T cells are not generated in the presence of cyclosporin A and, once activated, become inactivated or deleted when restimulated in the presence of this immunosuppressive drug.

关键词： 免疫应答   调节性   细胞   卵蛋白  

摘要： 调节性Ｂ－Ｂ细胞在卵蛋白的免疫应答中的相互作用［俄］／１９９５，１．－２１～２４抗原进入机体后，体内有相当数量的特异性的细胞克隆的激活，在体液免疫中。有ＴＨ细胞的介导，但也存在着Ｂ细胞的调节，而且是由Ｆａｂ段来完成，特别是独特型抗独特型的调节。该文以...