Antibody Binding to CD4 Induces Rac GTPase Activation and Alters T Cell Migration

The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4(+) and CD8(+) T cells in a tissue-specific manner. We reported that coreceptor therapy reverses diabetes in new onset NOD mice. A striking feature of coreceptor-induced remission is the purging of T cells from the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Abs binding to the coreceptors promotes T cell egress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4(+) T cells residing in the PLN of NOD mice. Anti-CD4 Ab treatment resulted in an increased frequency of PLN but not splenic CD4(+) T cells that exhibited a polarized morphology consistent with a migratory phenotype. Furthermore, PLN CD4(+) T cells isolated from anti-CD4 versus control Ab-treated animals displayed increased in vitro chemotaxis to chemoattractants such as sphingosine-l-phosphate and CXCL12. Notably, the latter was dependent on activation of the small Rho GTPases Racl and Rac2. Racl and Rac2 activation was increased in Ab-bound CD4(+) T cells from the PLN but not the spleen, and knockdown of Rac expression blocked the heightened reactivity of Ab-bound PLN CD4(+) T cells to CXCL12. Interestingly, Racl and Rac2 activation was independent of Rac guanine nucleotide exchange factors known to regulate T cell activity. Therefore, Ab binding to CD4 initiates a novel pathway that involves inflammation-dependent activation of Rac and establishment of altered T cell migratory properties. The Journal of Immunology, 2016, 197: 3504-3511.