title: ShcA regulates late stages of T cell development and peripheral CD4+ T cell numbers.
abstract: T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the β-selection stage, as well as via the TCR for selection from the CD4(+)CD8(+) double-positive stage to the CD4 or CD8 single-positive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the β-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed. In this study, we generated transgenic mice (CD4-Cre/ShcFFF mice) that specifically express a phosphorylation-defective dominant-negative ShcA mutant (ShcFFF) in late T cell development. Thymocytes in CD4-Cre/ShcFFF mice progressed normally through the β-selection checkpoint, but displayed a significant reduction in the numbers of single-positive CD4(+) and CD8(+) thymocytes. Furthermore, CD4-Cre/ShcFFF mice, when bred with transgenic TCR mouse strains, had impaired signaling through the transgenic TCRs. Consistent with defective progression to the single-positive stage, CD4-Cre/ShcFFF mice also had significant peripheral lymphopenia. Moreover, these CD4-Cre/ShcFFF mice develop attenuated disease in CD4(+) T cell-dependent experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Collectively, these data identify an important role for the adapter protein ShcA in later stages of thymic T cell development and in peripheral T cell-dependent events.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
authors.forename: Monica W
authors.initials: MW
authors.lastname: Buckley
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trampont
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
authors.forename: Sanja
authors.initials: S
authors.lastname: Arandjelovic
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Fond
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
authors.forename: Ignacio J
authors.initials: IJ
authors.lastname: Juncadella
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908 Ravi@virginia.edu.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins / Q000276:immunology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1