Mislocalization of SLP-76 leads to aberrant inflammatory cytokine and autoantibody production.
Central and peripheral tolerance is required to prevent immune responses to self-antigens. We now present a mouse model in which wild-type (WT) SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) has been constitutively targeted to the membrane, where CD4+ T cells become spontaneously dysregulated and develop an inflammatory phenotype. Mice bearing membrane-targeted SLP-76 (MTS) have a partial T-cell lymphopenia and impaired signaling though the mature T-cell receptor. The CD4+ T cells that develop in these mice possess an activated-like phenotype and are skewed toward the inflammatory T(H)1 and T(H)17 lineages. MTS mice also spontaneously develop autoantibodies at an early age. To rule out abnormal thymic selection as the sole cause of the MTS phenotype, we expressed WT SLP-76 along with the MTS followed by deletion of the WT allele in peripheral T cells. The peripheral MTS-expressing T cells demonstrate skewed cytokine responses when transferred into lymphopenic hosts. Thus, the abnormal effector T-cell phenotype still occurs in the presence of preserved central and peripheral tolerance, suggesting that diminished T-cell receptor signaling can promote skewed T-cell responses.
Sonnenberg
Gregory F
GF
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mangan
Paul R
PR
Bezman
Natalie A
NA
Sekiguchi
Debora R
DR
Luning Prak
Eline T
ET
Erikson
Jan
J
Maltzman
Jonathan S
JS
Jordan
Martha S
MS
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D002452:Cell Count; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis*; D017353:Gene Deletion; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D051379:Mice; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D016207:Cytokines; D018836:Inflammation Mediators; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins