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

Abstract

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-1-phosphate and CXCL12. Notably, the latter was dependent on activation of the small Rho GTPases Rac1 and Rac2. Rac1 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, Rac1 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.

DOI: 10.4049/jimmunol.1501600

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@article{Morillon2016AntibodyBT, title={Antibody Binding to CD4 Induces Rac GTPase Activation and Alters T Cell Migration.}, author={Yves Maurice Morillon and Elizabeth Chase Lessey-Morillon and Matthew Clark and Rui Zhang and Bo Wang and Keith W. T. Burridge and Roland M. Tisch}, journal={Journal of immunology}, year={2016}, volume={197 9}, pages={3504-3511} }