Expression and Functional Importance of Collagen-Binding Integrins, α1β1 and α2β1, on Virus-Activated T Cells

Abstract

Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, α1β1 and α2β1, on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of α1β1 and α2β1 can be rapidly induced on acutely activated T cells, that expression of α1β1 remains elevated on memory T cells, and that expression of α1β1 parallels that of viral-specific effector CD8+ T cells (defined by tetramer and IFN-γ staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of α1-deficient activated/memory T cells. Thus, expression of α1β1 and α2β1 integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of α1β1 blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues.

Functional Specialization of Memory Th Cells Revealed by Expression of Integrin CD49b

“…In contrast to CD4 ϩ memory T cells, our data suggest that only a small percentage of CD8 ϩ memory T cells display CD49b expression. This finding is in line with previous reports, in which CD49b expression in virus-specific CD8 ϩ T cells was found to be transient and following resolution of the acute infection CD49b ϩ CD8 ϩ memory T cells were reduced in proportion or completely disappeared (31)(32)(33). More recently, significant CD49b expression in CD8 ϩ memory T cells was shown to be maintained for more than a year after viral infection, which was however reduced, compared with earlier time points (34).…”

“…Collagen receptors on T cells have been implicated in T cell migration into and through peripheral tissues, their ability to induce inflammation at these sites and also protection against acute viral infection (33, 37). However, most of these effects were mediated by the collagen receptor VLA-1, instead of VLA-2, expressed in CD8 ϩ memory T cells (33,37). These findings are supported by the fact that, in contrast to the transient expression of VLA-2, expression of VLA-1 is permanently induced in the majority of CD8 ϩ memory T cells (31)(32)(33).…”

“…However, most of these effects were mediated by the collagen receptor VLA-1, instead of VLA-2, expressed in CD8 ϩ memory T cells (33,37). These findings are supported by the fact that, in contrast to the transient expression of VLA-2, expression of VLA-1 is permanently induced in the majority of CD8 ϩ memory T cells (31)(32)(33). The migration pattern of resting memory Th cells seems to be largely independent of CD49b expression, as the relative representation of CD49b Ϫ and CD49b ϩ memory Th cells is similar between lymphoid and most extralymphoid tissues.…”

“…Despite that, reactivity with the DX5 mAb (which recognizes the CD49b integrin (22)) was originally considered to be an NK cell-specific property. Recently, CD49b expression in conventional CD4 ϩ and CD8 ϩ T cells during viral infections has also been reported (31)(32)(33), in conjunction with (31) or separately from (32) expression of other NK cell-related molecules, such as NK1.1. Our data show that CD49b expression can be stably induced in a large proportion of conventional monoclonal TCR-transgenic and polyclonal memory Th cells, independently of any other NK cell-related molecule.…”

Collagen Distribution and Expression of Collagen-Binding α1β1 (VLA-1) and α2β1 (VLA-2) Integrins on CD4 and CD8 T Cells during Influenza Infection

“…This is at odds with the simple interpretation that CD49b expression correlates with Th1 and Th2 phenotypes among CD4 T cells (38,39). Similar expression of CD49a and CD49b was observed on CD8 ϩ T cells responding to lymphocytic choriomeningitis virus infection in the spleen (40).…”