Integrin-dependent role of human T cell matrix metalloproteinase activity in chemotaxis through a model basement membrane

Abstract

Human T lymphoblastoma cells of the CD4+ 8+ Tsup-1 line, that express alpha 4 and alpha 5 but not alpha 6 integrins of the beta 1 family, and CD4+ human blood T cells bind vasoactive intestinal peptide (VIP) with high affinity, leading to increased adherence, secretion of matrix metalloproteinases (MMPs), and chemotaxis. VIP-enhanced adherence of T cells to fibronectin was inhibited significantly by neutralizing monoclonal antibodies to beta 1 > alpha 4 > > alpha 5, but not to alpha 6. Antibodies to beta 1 and alpha 4 suppressed to a similarly significant extent VIP stimulation of both MMP-dependent T cell chemotaxis through fibronectin-enriched Matrigel and T cell degradation of 3H-type IV collagen in the Matrigel, without affecting VIP-evoked secretion of MMP by suspensions of T cells. The lesser inhibition of VIP-enhanced adherence of T cells to fibronectin by anti-alpha 5 antibody, than antibodies to beta 1 or alpha 4 chains, was associated with lesser or no suppression of MMP-dependent T cell chemotaxis through Matrigel and T cell degradation of type IV collagen in the Matrigel in response to VIP. Specific beta 1 integrins thus mediate interactions of stimulated T cells with basement membranes, including adherence, localized digestion by MMPs, and chemotactic passage, that promote entry of T cells into extravascular tissues.

Location, Location, Location: The Impact of Migratory Heterogeneity on T Cell Function

“…Initial interactions with the endothelial layer could upregulate MMP expression in T cells during transmigration (78–81). MMP2 and MMP9 production in T cells can be induced by ligation of integrins (α L β 2 , α 4 β 1 , α 5 β 1 , α V β 1 ) following interaction with the endothelial layer (e.g., ICAM, VCAM) or constituents of the basement membrane (e.g., fibronectin) (80–86). Depending on the type of integrin, differential MMP expression can be induced in T cells (80).…”

“…It is becoming increasingly appreciated that microanatomical location can be critical in determining the signals that T cells receive during activation (86), but perhaps also during homeostasis and transition to memory. For example, T cells that are in proximity to the lymphatic vessels in the LN have ready access to antigens and pro-inflammatory cytokines that drain from sites of infection (117).…”

Selectivity of Effects of Vasoactive Intestinal Peptide on Macrophages and Lymphocytes in Compartmental Immune Responsesa

“…In contrast, the stimulation of adherence of human cultured T cells and blood CD4 + T cells to fibronectin and of their chemotaxis through fibronectin‐enriched basement membranes by VIP in vitro was dependent on activation of T‐cell‐surface VLA‐4 (integrin α4 β1), as evidenced by the suppressive effects of neutralizing monoclonal antibodies to the α4 and β1 chains 51 (Fig. 1).…”

“…First, VIP evokes T‐cell migration through basement membranes and connective tissues by increasing expression of adhesive proteins, stimulating chemotaxis, and inducing secretion of specific matrix metalloproteinases (MMPs). 49–51 Second, concentrations of SP and VIP that are attained in tissues mounting immune responses enhance and inhibit T‐cell production and secretion, respectively, of IL‐2, IL‐4, IL‐10, and, in some instances IFN‐γ. 52–54 Third, both VIP and SP alter Ig production with isotypic selectivity.…”

“…SP and VIP both facilitate interactions of T cells with endothelium and connective tissues by increasing expression of P‐ and E‐selectins, 60 whereas in most cases only VIP enhances T‐cell β1‐integrin activation 51 and binding to type 1 vascular cell adhesion molecule (VCAM‐1) and fibronectin 50,61 (Fig. 1).…”