Collagen type I stimulates T cells

T lymphocytes interact with extracellular matrix proteins (ECMPs) through the ?-1 or very late antigen (VLA) integrins. VLA integrins comprise a common ? chain with different a-subunits that influence ECMP-binding specificity. They are costimulatory molecules, involved in adhesion and cellular migration. Reports on the role of the ECMP fibronectin in costimulating T cells have described therapeutic effects of VLA antibodies or peptide ligands in inflammatory/autoimmune disease models or transplantation. In contrast, the ECMP type I collagen has inconsistent effects on T cell activation, with most reports finding that resting peripheral blood (PB) T cells do respond. However, here the authors suggest that resting PB T cells are not representative of populations of extravascular, activated, effector cells that encounter immobilised ECMPs and that are involved in the pathogenesis of inflammatory/autoimmune diseases. To address this they have investigated the costimulatory effects of ECMPs on both freshly isolated human PB CD4⁺ and CD8⁺ T cells, and antigen- or mitogen-stimulated CD4⁺ and CD8⁺T cell lines used as models of the extravascular effector cells encountered in disease.

This work is largely based on in vitro proliferation assays using triplicate cultures, but no error bars are shown. As shown previously, PB CD4⁺ and CD8⁺ T cells proliferated in response to co-immobilised anti-CD3 and fibronectin, but not other ECMPs. In contrast, CD4⁺ and CD8⁺ T-cell lines proliferated in response to co-immobilised anti-CD3 with type I collagen, type III collagen, laminin or fibronectin. Similarly, immobilised type I collagen and fibronectin were costimulatory for antigen-induced T-cell line proliferation, using model antigen tetanus toxoid. However, type I collagen did not affect tetanus toxoid stimulation of fresh PB T cells. FACS analyses showed enhanced expression of a-1, 2 and 3 integrins on T cell lines. Experiments with blocking monoclonal antibodies to VLA-1 or VLA-2 or ?-1 integrins inhibited the response to type I collagen. Data suggested that the main T cell costimulatory activity was contained within the a-1 chain of type I collagen. Taken together these results demonstrate the costimulatory effect of type I collagen on both CD4⁺ and CD8⁺human T-cell lines, but not fresh PB T cells. The data show the type I collagen effect is mediated via VLA-1 and VLA-2 integrins.

The authors use CD4⁺ and CD8⁺ T cell lines as models of extravascular effector cells, although it is not clear that such lines are true representatives of activated effector T cells. However, the results demonstrate the potential importance of type I collagen, a very abundant extracellular matrix protein. The authors suggest that type I collagen is a more potent stimulus than the other ECMPs studied here (on a ?g/ml basis), although it is not clear if this is true at molar equivalents. The data suggest that therapeutic interventions targeted at interactions between T cells and ECMPs should include blockade of collagen.

Proliferation assays, FACS analysis, human T-cell preps, HPLC, SDS-PAGE, amino acid sequencing