title: Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses.
abstract: The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.forename: Evann
authors.initials: E
authors.lastname: Corbo
authors.forename: Michelle
authors.initials: M
authors.lastname: Schmidt
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Smith-Garvin
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Riese
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
authors.forename: Terri M
authors.initials: TM
authors.lastname: Laufer
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Maltzman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D013629:Tamoxifen