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-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.
Department of Microbiology & Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Y Maurice
YM
Morillon
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Elizabeth Chase
EC
Lessey-Morillon
Department of Microbiology & Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Matthew
M
Clark
Department of Microbiology & Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Rui
R
Zhang
Department of Microbiology & Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Bo
B
Wang
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.|McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Keith
K
Burridge
Department of Microbiology & Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA.
Roland
R
Tisch
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D054377:Chemokine CXCL12; D008246:Lysophospholipids; D009479:Neuropeptides; D013110:Sphingosine; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C060506:sphingosine 1-phosphate
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