Extracellular matrix proteins, regulators of T-cell functions in healthy and diseased individuals

Abstract

Antigen-dependentT-cellactivationrequiresengagementof the T-cell receptor (TCR)-CD3 complex with peptides presented by major histocompatibility complex molecules. However, stimulation of T cells through the complex of T-cell antigen receptor and CD3 in the absence of other signals is insufficient for optimal interleukin-2 (IL-2) production and proliferation and induces T-cell anergy. Therefore, additional costimulatory signals are needed for an effective T-cell-mediatedimmuneresponse.Suchsignalscanbeprovidedbyvarious interactions between T cells and ligands on antigen-presenting cells (e.g., CD2-CD58 [LFA-3] and CD28-CD80 [B7] cells [2, 59]). Furthermore, recent data indicate that the extracellular matrix (ECM) proteins can mediate strong costimulation in theprocessofT-cellactivationintheabsenceofmonocytes,so one could view the ECM protein as an equivalent of an antigen-presenting cell. This view is further strengthened by observations that ECM proteins can interact with both an integrin and other T-cell-activating agents (e.g., cytokines) (26, 29). Lymphocyte extravasation into the lymphatic tissue constitutes a normal physiological process by which the cells return finally to blood through the thoracic duct. This migration is associated with lymphocyte interaction with the ECM proteins present in the basement membranes (collagen type IV [C-IV] and laminin), because once the cells reach the underlying tissue they come into contact with interstitial ECM proteins (collagentypeI[C-I]andfibronectin[FN]).Thelatterinteractions appear to be especially relevant at sites of tissue invasion by inflammatory cells, because both C-I and FN are ubiquitous in interstitialECMproteins.Inaddition,FNhasbeenreportedto be produced by mononuclear cells themselves (monocytes and T cells), and its increased concentrations are found at the foci of inflammation and in sites of delayed-type hypersensitivity (34, 58). Therefore, it could be expected that the ECM proteins may regulate T-cell functions under both physiological and pathological conditions. (The biochemical structures of major ECM proteins were recently reviewed [48].) Evidence that integrins mediate information transfer into T cells is accumulating: occupation of integrin receptors by their ligands leads to tyrosine phosphorylation, elevation of cytoplasmic pH and Ca 21 concentration, activation of protein kinases, and inositol release. Moreover, FN binding via VLA-5 induces the AP-1 transcription factor necessary for IL-2 transcription.Integrinreceptors,byrecognizingECMproteins,can provide the signal for the stimulation of cytokine genes and subsequent cytokine production by T cells (this was demonstrated for IL-1, IL-2, and IL-4 and tumor necrosis factor alpha). Recent minireviews have provided a detailed analysis of ‘‘inside-to-out’’ and ‘‘outside-to-in’’ signaling by integrins (10, 29, 32, 48). Interestingly, recent data suggest that ECM protein-mediated cytokine gene activation can also occur in the absence of TCR engagement. This pathway of antigen-independent cytokine production by T cells interacting with the ECM proteins could be particularly important for gdT cells, frequently identified at sites of inflammation and thought to play an immunoregulatory rather than an effector role in the immune response (56). FewstudieshaveinvestigatedthefunctionsofECMproteins and integrins involved in T-cell development. These proteins are present in the thymic parenchyma and basement membranes and may be found to be associated with the epithelial cells which secrete them. Up to 15% of unseparated thymocytes adhere to FN, but 70% of the CD4 2 CD8 2 (double negative) cells do. In addition, thymocytes adhere to thymic stromal cells interacting with the FN present on their surfaces. Blocking of this adhesion (with anti-FN antibody and antiVLA-4 and anti-VLA-5 reagents) causes a potent inhibition of thymocyte differentiation in vitro. Thus, thymocyte-FN interactions may be critical in inducing and supporting the differentiation of immature T cells. In addition, another integrin (a6b4), with unknown ligand specificity, may play a role in intrathymic T-cell differentiation (63, 64). Recently, it was shown that human thymocyte proliferation induced by CD3 can be enhanced by ECM proteins in the presence of an additional signal: IL-2 or phorbol myristate acetate (61).