T细胞相关趋化因子及受体的研究进展

T细胞在发育、成熟、活化及发挥生物学效应的各个阶段表达不同的趋化因子受体。T细胞相关趋化因子及其受体的表达在不同的细胞类群上具有时相和分布的差异,并通过趋化因子与其受体特异性结合的模式,参与T细胞的发育过程,调控细胞的定向迁移,从而影响局部甚至整个机体的免疫状态。此外,它还在炎症、感染、肿瘤、自身免疫疾病等众多病理生理的过程中发挥重要作用。在这一领域的深入研究将为相关疾病的预防和治疗提供新的思路和途径。     

Secondary lymphoid-tissue chemokine induced modulation of T cells

In this study we were interested in investigating the extent to which stimulation through a chemokine receptor could modulate TCR function. We report that splenic T cells exposed to secondary lymphoid-tissue chemokine (SLC, CCL21) for 72, but not 2 or 24 hours, exhibited a decreased ability to produce IFN-gamma following CD3 crosslinking. Similar findings were observed with CCL2 and CCL5. The decrease in IFN-gamma production was not attributed to a decrease in T cell viability, was not accompanied with an increase in IL-4 production, and could be induced using a G protein coupled receptor agonist indicating involvement of chemokine receptors. One explanation for these findings was that following chemokine exposure the T cells were less efficient at TCR capping and exhibited a decrease in ZAP-70 protein expression. Consequently, these data indicate that CCL21 could modulate the function and expression of proteins necessary for T cell activation.     

Fractalkine and macrophage-derived chemokine: T cell-attracting chemokines expressed in T cell area dendritic cells.

Dendritic cells (DC) are a system of antigen-presenting cells specialized in interaction with T cells. Recently it has been reported that DC can produce CC (beta) chemokines that attract T cells. In this study we isolated mouse fractalkine and macrophage-derived chemokine (MDC) belonging to CX3C (delta) and CC chemokine families, respectively, from bone marrow-derived mature DC. While expression of fractalkine, which has so far been only examined in the brain and in vitro endothelial cells so far, was rather ubiquitous, MDC, which has been reported to be synthesized by macrophages and DC, was expressed specifically in the thymus and lymph node. This is the first report that indicates fractalkine expression by DC. Expression of fractalkine and MDC mRNA increased with maturation of DC during in vitro culture of bone marrow cells. Spleen- and epidermis-derived mature DC in culture also expressed these chemokines. Furthermore, their expression was detected selectively by Northern hybridization in CD11c+ B220- DC freshly purified from lymph nodes, and in large stellate cells in the lymph node T cell areas by in situ hybridization. Conditioned media of 293T cells transfected with these chemokine cDNA were chemotactic to Con A-activated splenic T cells as well as the mouse T cell line EL4. In conclusion, while fractalkine and MDC belong to different families of chemokines, both may be involved in recruitment of T cells for interaction with mature DC in the immune response.     

Leishmania major modulates chemokine and chemokine receptor expression by dendritic cells and affects their migratory capacity

Dendritic cells (DC) both produce and respond to chemokines. We examined the profiles of chemokines and chemokine receptors expressed by DC and their chemotactic response after interaction with Leishmania major. Expression of the chemokine receptors CCR2 and CCR5 by DC and their responsiveness to the respective ligands, CCL2 and CCL3, were downregulated, while the level of CCR7 and the DC response to its ligand CCL21 were enhanced. These parasite-induced alterations were observed with DC from L. major-resistant and -susceptible mice. In contrast, expression of the chemokine CXCL10 was elicited only in DC from L. major-resistant mice.     

The changing preference of T and B cells for partners as T-dependent antibody responses develop

Summary: Recirculating virgin CD4⁺ T cells spend their life migrating between the T zones of secondary lymphoid tissues where they screen the surface of interdigitating dendritic cells. T-cell priming starts when processed of interdigitating dendritic cells. T-cell priming starts when processed peptides or superantigen associated with class II MHC molecules are recognised. Those primed T cells that remain within the lymphoid tissue move of the outer T zone, where they interact with B cells that have taken up and processed antigen. Cognate interaction between these cells initiates immunoglobulin (Ig) class swith-recombination and proliferation of both B and T cells; much of this growth occurs outside the T zones. B cells both B and T cells; much of this growth occurs outside the T zones. B cells migrate to follicles. Where they form germinal centres, and to extrafollicular sites of B-cell growth, where they differentiate into mainly short-lived plasma cells. T cells do not move to the extrafollicular foci but to the follicles; there they proliferate and are subsequently involved in the selection of B cell that have mutated their Ig variable-region genes. During primary antibody responses T-cell proliferation in follicles produces many times the peak number of T cell found in that site; a substantial proportion of the CD4⁺ memory T-cell pool may originate from growth in follicles.     

自然杀伤性T细胞在恶性胸腔积液疾病中的分布及其趋化因子受体的表达和意义

目的比较肺癌胸膜转移所引起的恶性胸腔积液(malignant pleural effusion,MPE)疾病中的NKT细胞的分布,及其趋化因子受体CCRs的表型,检测NKT细胞及相关趋化因子受体(CCRs)的分布情况及意义。方法四色流式细胞检测技术检测恶性胸腔积液、同源外周血(peripheral blood,PB)、结核性胸腔积液(tuberculous pleural effusion,TPE)和健康对照组(healthydonor,HD)中TCR-Vα24+TCR-Vβ11+的NKT细胞比例,及MPE、PB和HD的NKT细胞膜趋化因子受体CCR2,CCR4,CCR5和CCR6表达情况。结果①恶性胸腔积液NKT比例(0.98%±0.08%)高于外周血(0.71%±0.06%)和良性胸腔积液(0.72%±0.06%)(P=0.009,P=0.018);与和健康对照组相比均无统计学差异(P>0.05)。健康对照组血样标本的NKT比例(1.13%±0.09%)显著高于疾病组血样,(P=0.001)。②在MPE、PB及HD三组标本中,NKT表达CCRs比例分别为:CCR2(MPE 28.14%±8.41%、PB 34.44%±4.30%、HD 34.37%±3.54%),CCR4(MPE 40.52%±4.10%、PB 65.21%±4.83%、HD 57.10%±5.28%),CCR5(MPE 32.36%±4.10%、PB 26.45%±5.10%、HD 14.31%±3.05%)及CCR6(MPE 19.37%±6.22%、PB 22.15%±7.21%、HD 17.29%±3.43%),其中各项CCRs比例作两两比较:CCR4在PB中显著高于在MPE中的表达(P<0.05);与HD无统计学差异。CCR5在MPE中显著高于在PB中的表达(P<0.05);与HD相比无统计学差异。CCR2和CCR6在3份标本中均无统计学差异(P>0.05)。结论恶性胸腔积液中NKT细胞比例上调,高于同源外周血及良性胸腔积液,NKT细胞在恶性胸腔积液局部具有聚集,可能与其强大的抗肿瘤作用相关。恶性胸腔积液、同源外周血及健康对照组中的NKT细胞均表达一定比例的CCR2、CCR4、CCR5和CCR6分子,其中CCR4和CCR5的比例有所变化,提示CCR4和CCR5可能参与NKT细胞趋化活动。     

Adolescents' anxiety in dating situations: the potential role of friends and romantic partners.

This study examined adolescents' interpersonal functioning, including the qualities of their closest friendships and romantic relationships, as predictors of dating/heterosocial anxiety. An ethnically diverse sample of 781 adolescents (57% girls; ages 15-19 years) completed measures that assessed the number and type of close friends, the presence of a romantic relationship, the qualities of their best same-sex friendship and their romantic relationship (using the Network of Relationships Inventory-Revised), and levels of dating or heterosocial anxiety (using the Dating Anxiety Scale for Adolescents). Most adolescents were romantically involved, and girls were more likely to have a romantic partner than boys. Adolescents with fewer other-sex friends and those with less positive and more negative interactions with their best friends reported high levels of dating anxiety. In addition, adolescents who reported never having a romantic relationship, who did not have a current romantic partner, and who had less positive and more negative interactions with their romantic partners reported higher levels of dating anxiety. Variations were noted for different aspects of dating anxiety. The findings indicate that multiple aspects of adolescents' social relations may be independently and uniquely related to feelings of distress in dating or heterosocial situations. Adolescents' social relationships have the potential to support or interfere with the development of successful romantic relationships.     

T regulatory cells and their counterparts: masters of immune regulation

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4⁺ T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.     

The ratio between dendritic cells and T cells determines the outcome of their encounter: proliferation versus deletion

Dendritic cells (DC) either induce T cell tolerance or contribute to the initiation and modulation of T and B cell responses. Since many of the variables determining the thresholds of naive T cell priming were defined in vitro using a homogeneously matured DC population, we here focused on partially mature DC which might reflect the occurrence of tumor-infiltrating and thymic DC. To predict how those DC regulate the induction of antigen-specific T cell proliferation and T cell tolerance, we co-cultured ovalbumin-pulsed murine DC at different ratios with antigen-specific DO11.10 transgenic T cells. Whereas partially mature DC at a DC/T cell ratio of 1:10 supported proliferation, a DC/T cell ratio of 1:2 induced proliferation arrest in naive CD4+ T cells. The acquisition of the NK cell inhibitory markers NK1.1 and KLRG on T cells exposed to high numbers of DC suggests a role for these molecules in the protection of antigen-responsive T cells from exhaustion by overstimulation. Mechanistically, abortive T cell proliferation upon encounter of high numbers of partially mature DC is caused by an apoptosis-related pathway, suggesting that excessive antigen density without sufficient costimulation results in activation-induced cell death.     

Chemokines,chemokine receptors and CD4+CD25+ regulatory T cells

The fields of regulatory T (Treg) cells and chemokines/chemokine receptors have progressed rapidly in the last few years. Treg cells, especially CD4⁺CD25⁺ Treg cells, play a critical role in maintaining self-tolerance and immune homeostasis. Chemokines and chemokine receptors are crucial for lymphoid development, homing and immunological regulation. This review will discuss the biological effects of chemokines and chemokine receptors on regulating the migration and development of CD4⁺CD25⁺ Treg cells, and the potential clinical implications of these findings when considering chemokine receptors as therapeutic targets.     

T cells and their eons-old obsession with MHC

T cells bearing receptors made up of α and β chains (TCRs) usually react with peptides bound to major histocompatibility complex proteins (MHC). This bias could be imposed by positive selection, the phenomenon that selects thymocytes to mature into T cells only if the TCRs they bear react with low but appreciable affinity with MHC + peptide combinations in the thymus cortex. However, it is also possible that the polypeptides of TCRs themselves do not have random specificities but rather are biased toward reaction with MHC. Evolution would therefore have selected for a collection of TCR variable elements that are prone to react with MHC. If this were to be so, positive selection would act on thymocytes bearing a pre biased collection of TCRs to pick out those that react to some extent, but not too well, with self MHC + self-peptides. A problem with studies of this evolutionary idea is the fact that there are many TCR variable elements and that these differ considerably in the amino acids with which they contact MHC. However, recent experiments by our group and others suggest that one group of TCR variable elements, those related to the mouse Vβ8 family, has amino acids in their CDR2 regions that consistently bind a particular site on an MHC α-helix. Other groups of variable elements may use different patterns of amino acids to achieve the same goal. Mutation of these amino acids reduces the ability of T cells and thymocytes to react with MHC. These amino acids are present in the variable regions of distantly related species such as sharks and human. Overall the data indicate that TCR elements have indeed been selected by evolution to react with MHC proteins. Many mysteries about TCRs remain to be solved, including the nature of auto-recognition, the basis of MHC allele specificity, and the very nature and complexity of TCRs on mature T cells.     

Generation of effector CD8+ T cells and their conversion to memory T cells

Summary: Immunological memory is a cardinal feature of adaptive immunity. We are now beginning to elucidate the mechanisms that govern the formation of memory T cells and their ability to acquire longevity, survive the effector-to-memory transition, and mature into multipotent, functional memory T cells that self-renew. Here, we discuss the recent findings in this area and highlight extrinsic and intrinsic factors that regulate the cellular fate of activated CD8⁺ T cells.     

The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7

Secondary lymphoid-tissue chemokine, SLC, also known as exodus-2 and 6Ckine, is a novel CC chemokine with selectivity for T lymphocytes and preferential expression in lymphoid tissues. We have studied its production, receptor usage and biological activities. High levels of SLC mRNA were detected in lymph nodes, the gastrointestinal tract and several gland tissues, but no expression was found by Northern blot analysis in freshly isolated or stimulated blood monocytes and lymphocytes, or neutrophils and eosinophils. In situ hybridization revealed constitutive expression of SLC in the T cell areas and the marginal zone of follicles in lymph nodes and the mucosa-associated lymphoid tissue, but not in B cell areas or sinuses. Comparison with immunocytochemical staining showed similarity between the in situ expression of SLC and the distribution of interdigitating dendritic cells but not with sinus-lining dendritic cells, macrophages or T lymphocytes. SLC induced chemotaxis of T lymphocytes and its activity increased considerably when the cells were conditioned with IL-2 or phytohemagglutinin (PHA). Under optimal conditions SLC had unusually high efficacy and induced the migration of up to 50 % of input T lymphocytes. SLC also induced Ca²⁺ mobilization in these cells. Similar responses were obtained with EBI1 ligand chemokine (ELC), and sequential stimulation with both chemokines led to cross-desensitization, suggesting that SLC acts via the ELC receptor, CCR7. This was confirmed using murine pre-B cells stably transfected with CCR7 which bound SLC with high affinity and showed chemotaxis and Ca²⁺ mobilization in response to both SLC and ELC. In T lymphocytes PHA and IL-2, which enhanced chemotactic responsiveness, also markedly enhanced CCR7 expression. In contrast to all known chemokine receptors, up-regulation of CCR7 by IL-2 was transient. A maximum was reached in 2 – 3 days and expression returned to initial levels within 8 – 10 days. The present study shows that SLC is constitutively produced within the T cell areas of secondary lymphoid organs and attracts T lymphocytes via CCR7.     

Human cytomegalovirus-specific cytotoxic T cells: their precursor frequency and stage specificity

Human virus-specific cytotoxic T (Tc) cells may be important in maintaining the virus/host equilibrium during persistent herpes virus infections such as that with human cytomegalovirus (HCMV). We have previously shown that HCMV-specific Tc cells are present in peripheral blood in normal asymptomatic seropositive individuals (L. K. Borysiewicz et al., Eur. J. Immunol. 1983. 13: 804). In this study we have used limiting dilution analysis to estimate the precursor frequency of these Tc cells and to further delineate their specificity for viral proteins expressed at different stages of the virus replicative cycle. HCMV-specific Tc precursor cells were present in peripheral blood lymphocytes (PBL) at a frequency of 1/5000 to 20,000 E+ PBL. This frequency was higher than that observed for varicella-zoster virus (VZV)-specific Tc cells (1/30,000 to greater than 500,000) in asymptomatic individuals and was similar to the VZV Tc precursor cell frequencies observed following clinical reactivation (1/30,000). When the stage specificity of clonally derived HCMV-specific Tc cells was analyzed, using target cells treated with phosphonoformate to allow expression of only the nonstructural viral proteins, the majority (60%) of Tc cells lysed these cells. A number of Tc cells lysed only cells which expressed the structural or late HCMV proteins. These results suggest a high precursor frequency of HCMV-specific Tc cells in PBL, and that there are subpopulations of such Tc cells specific for HCMV antigens expressed at different stages of the virus replicative cycle. However, the relative frequencies of these subpopulations suggest that the immunodominant HCMV antigens with respect to the Tc response are expressed at immediate early and/or early times.     

Lysophosphatidylcholine up-regulates CXCR4 chemokine receptor expression in human CD4 T cells

Oxidized low-density lipoprotein (OxLDL) is an inflammatory modulator in the atherosclerotic plaque. We examined the effect of lysophosphatidylcholine (lysoPC), a main phospholipid component of OxLDL, on inflammatory responses in human CD4 T cells. We found that lysoPC dose- and time-dependently increased expression of CXCR4, the chemokine receptor on CD4 T cells. This increase was inhibited by caffeic acid phenethyl ester or SN50, nuclear factor-kappaB inhibitors, and also by suppression of G2A expression, the specific receptor for lysoPC, using antisense oligonucleotide. lysoPC enhanced CD4 T cell chemotaxis in response to stromal cell-derived factor-1 (SDF-1), the exclusive ligand for CXCR4. lysoPC also enhanced SDF-1-stimulated production of inflammatory cytokines interleukin-2 and interferon-gamma by CD4 T cells activated by anti-CD3 immunoglobulin G. In conclusion, this study demonstrates that lysoPC directly modulates inflammatory responses in human CD4 T cells. The data suggest that the presence of lysoPC and SDF-1 in atherosclerotic lesions may trigger inflammatory responses mediated by CD4 T cells, which may play an important role in progression of atherosclerosis.