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

The use of nondepleting Absspecific for CD4 and CD8 is an effective strategy to tolerize CD4 + and CD8 + T cellsin 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 cellsfrom the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Absbinding to the coreceptors promotes T cellegress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4 + T cellsresiding in the PLN of NOD mice. Anti-CD4 Abtreatment resulted in an increased frequency of PLN but not splenic CD4 + T cellsthat exhibited a polarized morphology consistent with a migratory phenotype. Furthermore, PLN CD4 + T cellsisolated from anti-CD4 versus control Ab-treated animals displayed increased in vitro chemotaxis to chemoattractants such as sphingosine-1-phosphate and CXCL12. Notably, the latter was dependent on activation of the small Rho GTPases Rac1and Rac2. Rac1and Rac2 activation was increased in Ab-bound CD4 + T cellsfrom the PLN but not the spleen, and knockdown of Rac expression blocked the heightened reactivity of Ab-bound PLN CD4 + T cellsto CXCL12. Interestingly, Rac1and Rac2 activation was independent of Rac guanine nucleotide exchange factorsknown to regulate T cellactivity. Therefore, Abbinding to CD4 initiates a novel pathway that involves inflammation-dependent activation of Rac and establishment of altered T cellmigratory properties.