Regulation of integrin function by T cell activation

Lymphocyte adhesiveness is dynamically regulated in response to conditions in the extracellular environment. One mechanism of regulation of integrin adhesion receptors involves a rapid, but transient, increase in integrin function upon T lymphocyte activation. These integrin activating signals can be initiated either via ligation of Ig superfamily members that are coupled to tyrosine kinase cascades, such as the CD3/T cell receptor, CD2, and CD28, or by G proteincoupled receptors for chemokines. Analysis of integrin activation induced by CD3/TCR, CD2 and CD28 suggests a critical role for phosphoinositide 3-OH kinase (PI 3-K). This review summarizes recent insights into PI 3-K-dependent regulation of integrin function in leukocytes, including the mechanisms by which these receptors are coupled to PI 3-K, and potential downstream effectors of PI 3-K that regulate integrin-mediated adhesion in leukocytes.     

Regulation of T cell integrin function by adapter proteins

Integrins are cell surface heterodimers that bind adhesion molecules expressed on other cells or in the extracellular matrix. Integrin-mediated interactions are critical for T cell development in the thymus, migration of T cells in the periphery, and induction of T cell effector functions. In resting T cells, integrins are maintained in a low affinity state. Engagement of the T cell receptor or chemokine receptors increases integrin affinity, enabling integrins to bind their ligands and initiate a signaling cascade resulting in altered cell morphology and motility. Our laboratory is interested how adapter proteins, mediators of intracellular signal transduction, regulate both signals from the T cell receptor to integrins (inside-out signaling) and (outside-in) signals from integrins into the cell.     

T cell integrin activation by chemokines in inflammation

The adhesive function of integrins is regulated through cytoplasmic signaling induced by several stimuli, whose process is designated as "inside-out signaling". A large number of lymphocytes are recruited to the sites of inflammation where they form an essential component of the response to infection, injury, autoimmune disorders, allergy, tumor invasion, atherosclerosis and so on. The recruitment of leukocytes into tissue is regulated by a sequences of interactions between the circulating leukocytes and the endothelial cells. Leukocyte integrins play a pivotal role in leukocyte adhesion to endothelial cells. During the process, the activation of integrins by chemokines is essential for integrin-mediated adhesion in which a signal transduced to the leukocyte converts the functionally inactive integrin to an active adhesive configuration. The present review documents the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines during inflammatory processes.     

Regulation of TCR-mediated T cell activation by TNF-RII

In the present study, we investigated the role of tumor necrosis factor receptor II (TNF-RII) in human T cell activation induced via the T cell receptor (TCR) in an antigen-presenting cell-independent system. Our results confirm that interaction of TNF-alpha with TNF-RII but not TNF-RI is directly costimulatory to TCR-mediated T cell activation, thereby augmenting T cell proliferation, expression of T cell activation markers (CD25, human leukocyte antigen-DR, TNF-RII), and secretion of cytokines such as interferon-gamma and TNF-alpha. In contrast to the well-defined costimulatory molecule CD28, costimulation via TNF-RII showed significant differences in kinetics, requirement for cross-linking, redundancy of intracellular signaling pathways involved, and the capacity to induce interleukin (IL)-2, IL-10, and IL-13 secretion. In addition, cross-linking TNF-RII had the capacity to down-regulate TCR/CD28-induced Ca++ mobilization, IL-2 mRNA expression, and IL-2 and IL-10 secretion. Taken together, our findings demonstrate that TNF-RII plays a unique role among the T cell costimulatory molecules, as TNF-RII ligation can have positive and negative effects on TCR-dependent signaling. TNF-RII cross-linking has an inhibitory effect on early TCR signaling events proximal to induction of Ca++ flux, which ultimately leads to modulation of the T cell cytokine pattern expressed.     

Regulation of apoptosis and T cell activation by Fas-specific mAb

Fas was initially described as a molecule expressed on the surfaceof certain cell lines that could mediate programmed cell death(apoptosis) subsequent to ligatlon by specific mAb. To determinewhether mAb to other epitopes on the Fas molecule might mediateother functions, we generated a panel of mAb to the extracellularportion of human Fas. Significant lysis of Fas-expressing targetcells was only observed when the new mAb were first bound toa solid-phase support and not when the mAb were added in solution.However, several of these mAb inhibited the killing of targetcells induced by the prototypic Fas-specific mAb, CH-11. ThosemAb that inhibited apoptosis of target cells mediated by theCH-11 mAb also blocked lysis of target cells mediated by cellsexpressing Fas ligand. Finally, some of the Fas-specific mAbwere found to co-stimulate proliferation of peripheral bloodT cells in the presence of immobilized CD3 mAb. Thus, the dataindicate the existence of a complex set of interactions mediatedby Fas in both normal and transformed lymphoid cells that mayhave important implications regarding the role(s) of this moleculein regulation of immune responses.     

Signal transduction events regulating integrin function and T cell migration

Integrin receptors facilitate T cell function by mediating adhesive events critical for T cell trafficking and recognition of foreign antigen, including interactions with vascular endothelium, extracellular matrix components, and antigen-presenting cells. Consequently, the functional activity of integrin receptors is acutely regulated by various intracellular signals delivered by other cell surface receptors, resulting in rapid changes in T cell adhesion and migration. This review highlights recent insights into our understanding of the signaling events by which the CD3/T cell receptor complex and chemokine receptors regulate integrin function and T cell migration. These studies highlight novel functions for several signaling molecules, including the tyrosine kinases Itk and ZAP-70, and the adapter protein SLAP-130/Fyb. In addition, analysis of the regulation of integrin function and chemokine-mediated migration has highlighted the critical role that spatial localization of signaling molecules plays in signal transduction, and the importance of the actin cytoskeleton in T cell function.     

Regulation of in vitro and in vivo T cell activation by CD43

Accessory molecule interactions can be critical in determining the outcome of a T cell's encounter with antigen. Cell adhesion proteins may augment T cell responses by facilitating TCR engagement of the antigen-MHC complex, while co-stimulatory molecules may deliver distinct signals that modulate T cell responsiveness. CD43 (leukosialin, sialophorin) has been suggested to influence cell activation by steric hindrance based upon the large size and glycosylation of the protein, as well as the relative abundance of the protein on the cell surface. In this paper we examine both in vitro and in vivo T cell-dependent responses in CD43-deficient mice. We demonstrate that T cells from CD43-deficient mice are hyper-responsive following both in vivo and in vitro activation, and that this is observed in response to not only TCR-CD3-mediated stimulation, but also following receptor-independent activation. This data suggests that mechanisms other than non-specific steric hindrance are important in the regulation of T cell activation by CD43.      

Regulation of T cell function by Mtv-7 gene products.

Mls-1, a superantigen encoded by the endogenous mouse mammary tumor virus Mtv-7 induces immunological tolerance through deletion of antigen-reactive T cells. A remarkable difference between this self-antigen and self-MHC antigens is that while the mouse establishes tolerance against self MHC antigens by the time of birth it does not begin to delete T cells specific for the self-superantigen until they had mounted an immuneresponse against it. An immune response occurs normally several days after birth and may be delayed experimentally for weeks before the deletion process ensues. However, for effective deletion of Mls-1 reactive T cells the mouse must be exposed to Mtv-7 positive lymphoid cells within hours after birth. In reviewing here data obtained in this and other laboratories regarding experimental induction of Mls-1 tolerance in neonatal mice we are trying to make a case for the involvement of Mtv-7 encoded antigens distinct from the superantigen. We propose that T cells reactive with non superantigenic Mtv-7 determinants pose a threat to the establishment of chimaerism between Mls-1- neonates and Mls-1+ inocula, as they may cause the rejection of Mls-1 superantigen bearing lymphocytes. Chimaerism is essential for the establishment of lasting Mls-1 tolerance.     

Regulation of T follicular helper cell formation and function by antigen presenting cells

CD4+ T cells can differentiate into numerous subsets characterized by expression of a suite of cytokines and effector molecules that endow them with specialized functions. By mediating the differentiation of B cells into memory and plasma cells following exposure to T-dependent antigens (Ag), T follicular helper (TFH) cells have emerged as the predominant subset of CD4+ T cells responsible for regulating humoral immunity. The generation of TFH cells from na?ve precursors typically involves sequential cognate interactions with distinct populations of Ag-presenting cells (APCs): dendritic cells within the T-cell zone of lymphoid tissues, and activated B cells at the border of the T-zone and follicle, and then within a germinal center. Recent studies have illuminated the key roles of APCs in TFH development, and have also re-defined the role of B cells in this process.     

Genetic analysis of integrin activation in T lymphocytes

Summary: Among the myriad receptors expressed by T cells, the sine qua non is the CD3/T cell receptor (CD3/TCR) complex, because it is uniquely capable of translating the presence of a specific antigen into intracellular signals necessary to trigger an immune response against a pathogen or tumor. Much work over the past 2 decades has attempted to define the signaling pathways leading from the CD3/TCR complex that culminate ultimately in the functions necessary for effective T cell immune responses, such as cytokine production. Here, we summarize recent advances in our understanding of the mechanisms by which the CD3/TCR complex controls integrin-mediated T cell adhesion, and discuss new information that suggests that there may be unexpected facets to this pathway that distinguish it from those previously defined.     

Regulation of T cell function by NK cell receptors for classical MHC class I molecules

Inhibitory receptors for MHC class I molecules were initially characterised on NK cells. Human and mouse NK cell receptors (NKRs) are also expressed on T cells, predominantly on a subset of memory-phenotype CD8(+) T cells. This review focuses on the precise determination of interactions between NKRs and MHC class I, as well as on the unexpected in vivo function of NKRs on T cells.     

Regulation of human B cell activation and antibody production by non-major histocompatibility complex-restricted cytotoxic T lymphocytes

To determine whether non-major histocompatibility complex-restricted cytotoxic human T lymphocytes (NrCTL) are involved in the regulation of antibody response, we studied the effect of a CD3+, T cell receptor (TcR)-alpha/beta+, NKH1+ clone named JT9 on B cell proliferation and differentiation. It was found that low amounts of JT9 clone (5%) profoundly inhibited (greater than 80%) in vitro specific anti-trinitrophenyl primary antibody response. This inhibition did not need the presence of autologous T cells and took place at the induction phase of the antibody response. JT9 clone had no effect on resting B cells but enhanced proliferation of anti-mu-stimulated B cells. Respective involvements of cell to cell interaction, cytotoxicity and lymphokines were investigated. (a) The effect of monoclonal antibodies (mAb) inhibiting cytotoxic properties of JT9 clone, i.e. an anti-clonotypic structure mAb and a mAb directed against a target cell antigen similar to 4F2, were studied. These mAb did not reverse the effects of JT9 on B cell activation and differentiation. Thus, these contrasting effects of JT9 clone on B cell response did not seem to involve an interaction of JT9 clone TcR with its target or, further, cytotoxic properties for which this clone had been characterized. (b) Supernatant of JT9 clone stimulated by cross-linking of TcR complex, in the absence of interleukin 2, exerted a proliferative effect on anti-mu-stimulated B cells but not on resting B cells. These findings suggest that JT9 clone could secrete a B cell growth factor-like activity and that NrCTL cells may play an important role in the regulation of antibody response.     

Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning of CD8+ T cells based on {alpha}4 integrin expression

Systemic infection with lymphocytic choriomeningitis virus (LCMV)is accompanied by marked splenomegaly, primarily reflectingthe accumulation of CD8⁺ T cells with an activated phenotypee.g. VLA-4^hi). Analysis of DNA content using 7-aminoactinomycin-Drevealed that as many as 30% of CD8⁺ T cells are cycling aroundday 6 post-infection and that virtually all cycling cells expressa high level of VLA-4. In accord with the relatively stableCD4⁺ cell number, only few cycling CD4⁺ cells were observed.Following virus control, splenic lymphocyte numbers decreasedgradually and during this period many apoptotic cells were detectedin the white pulp using terminal deoxynucleotidyl transferase-mediateddUTP-biotin nick end labeling. Flow cytometric analysis of DNAcontent revealed a high frequency of cells with subnormal levelsof DNA in the CD8⁺VLA-4^hi subset, whereas the frequency waslow for other lymphocyte subsets studied (CD4⁺, CD8⁺VLA-4¹⁰and B cells). In addition, numbers of CD8⁺VLA-4^hi cells constitute{small tilde}30% of splenocytes at the peak of the responseand undergo preferential decrease during normalization of splenocytenumbers. Together these findings indicate that LCMV-inducedactivation of T cells is followed by apoptosis of many of theactivated cells. Those CD8⁺VLA-4^hi cells which do persist inLCMV Immune mice are more sensitive to treatment with the cell-cycle-specificdrug hydroxyurea than are phenotypically naive T cells. Ourresults therefore indicate that LCMV infection induces polyclonalactivation of CD8 ⁺ cells which is followed by apoptosis ofmost of the triggered cells while a smaller subset persistsas a primed population which include cycling cells.     

Regulation of mast cell activation by complement-derived peptides

It is known for more than 25 years that the complement-derived anaphylatoxic peptides, C3a, C4a and C5a are potent activators of basophils and certain types of mast cells. Although tissue distribution of receptors for C3a and C5a well exceeds myeloid cells, apparently they are not expressed on mucosal type mast cells, consequently these cells are not activated by C3a and C5a. Our results do however demonstrate that C3a and peptides related to this complement activation product are able to inhibit FcRI-clustering induced activation of mucosal type mast cells-such as RBL-2H3 cells and bone-marrow derived mast cells. Based on the current results we propose the presence of separate "activator" and "inhibitor" sequence motifs in C3a which are in balance under physiologic conditions.     

小鼠血小板/T细胞活化抗原1的表达分布与功能

目的研究小鼠血小板／Ｔ细胞活化抗原１（ＰＴＡ１）在小鼠组织及各种细胞系的表达分布与诱导,及其在杀伤性Ｔ细胞和ＬＡＫ细胞诱导中的作用。方法应用流式细胞仪技术分析ＰＴＡ１在小鼠组织及细胞系中的表达及诱导;用同种异体抗原诱导杀伤性Ｔ细胞,用ＩＬ－２诱导ＬＡＫ细胞,分别研究ＰＴＡ１特异性单克隆抗体对其分化的影响。结果小鼠ＰＴＡ１主要在Ｔ细胞系呈诱导性表达,参与杀伤性Ｔ细胞的分化,但不参与ＬＡＫ细胞的诱导。结论小鼠ＰＴＡ１与人ＰＴＡ１有相似的分布特点与功能,是一种进化中高度保守的白细胞分化抗原