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* Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455; and
Department of Medicine, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455
The hemopoietic specific adapter protein ADAP (adhesion and degranulation-promoting adapter protein) positively regulates TCR-dependent, integrin-mediated adhesion and participates in signaling pathways downstream of the TCR that result in T cell activation. The specific role of ADAP in regulating Ag-dependent T cell interactions with APCs and T cell activation following Ag stimulation is not known. We used ADAP–/– DO11.10 T cells to demonstrate that ADAP promotes T cell conjugation to Ag-laden APCs. Complementary in vitro and in vivo approaches reveal that ADAP controls optimal T cell proliferation, cytokine production, and expression of the prosurvival protein Bcl-xL in response to limiting Ag doses. Furthermore, ADAP is critical for clonal expansion in vivo independent of Ag concentration under conditions of low clonal abundance. These results suggest that ADAP regulates T cell activation by promoting Ag-dependent T cell-APC interactions, resulting in enhanced T cell sensitivity to Ag, and by participating in prosurvival signaling pathways initiated by Ag stimulation.
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1 This work was supported by National Institutes of Health Grants R01AI038474 (to Y.S.), R01AI031126 (to Y.S.), and R01AI056016 (to E.J.P.), a grant from the Arthritis Foundation (to E.J.P.), an American Heart Association predoctoral fellowship (to K.L.M.), and National Institutes of Health Training Grant T32DE007288 (to M.S.T. and B.J.B.). Y.S. is supported in part by the Harry Kay Chair in Biomedical Research at the University of Minnesota.
2 Current address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
3 Address correspondence and reprint requests to Dr. Yoji Shimizu, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, MMC 334/Room 6-112 NHH, 312 Church Street Southeast, Minneapolis, MN 55455. E-mail address: shimi002{at}umn.edu
4 Abbreviations used in this paper: ADAP, adhesion and degranulation-promoting adapter protein; CARMA1, caspase-recruitment domain (CARD)-membrane-associated guanylate kinase (MAGUK) protein 1; MAGUK, membrane-associated guanylate kinase; OVAp, OVA323–339 peptide; PFA, paraformaldehyde; PKC
, protein kinase C; SLP-76, SH2 domain-containing leukocyte-specfic phosphoprotein of 76 kDa.
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