THE INVASIN PROTEIN OF YERSINIA SPP PROVIDES COSTIMULATORY ACTIVITY TO HUMAN T-CELLS THROUGH INTERACTION WITH BETA-1 INTEGRINS

The invasin proteins of Yersinia spp. are outer membrane proteins whic h are involved in the penetration of these bacteria into mammalian cel ls (Cell 1990. 60: 861). Invasin binds to several different beta1 inte grins with extremely high affinity, the integrin-binding domain of inv asin has been mapped to the C-terminal 192 amino-acids of the molecule (J. Biol. Chem. 1991. 266: 24367). Expression of this fragment alone on the cell surface of non-invasive bacteria is enough to confer the i nvasive phenotype on these strains (EMBO J. 1990. 9: 1979). Here we sh ow that the carboxy-terminal 192 amino acids of invasin expressed as a fusion protein with the maltose binding protein of E. coli is capable of delivering co-stimulatory signals to human T cells through the bet a1 integrins. Co-stimulation was assayed by the ability of invasin to augment the response of highly purified CD4+ and CD8+ T cells to co-im mobilized anti-CD3 antibody. Antibody blocking studies indicated that the co-stimulation was mediated through beta1 integrins. The prolifera tion induced by co-stimulation of CD4+ T cells was accompanied by the synthesis of the cytokines tumor necrosis factor-alpha and interferon- gamma, whereas the activation of CD8+ T cells led to the generation of cytotoxic effectors. The region of the invasin molecule involved in T cell activation was further mapped using synthetic peptides. A region of the invasin molecule containing the residues TAKSKKFPSY could subs titute for invasin in T cell activation. The co-stimulation by peptide could also be inhibited by anti-integrin antibodies. The observation that an outer membrane protein of a bacterium which is associated with reactive arthritis and other autoimmune spondyloarthropathies can act as a T cell co-stimulus may have implications for the etiology of the se diseases.