title: SLAM-SAP signaling promotes differentiation of IL-17-producing T cells and progression of experimental autoimmune encephalomyelitis.
abstract: IL-17 plays critical roles in host defenses, combating bacterial and fungal infections, as well as the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). The signaling adaptor SAP is essential for normal immune homeostasis and mutations within SH2D1A, the locus encoding this protein, result in serious and sometimes fatal syndromes, including X-linked lymphoproliferative disease and severe cases of common variable immunodeficiency. However, the precise cellular basis of how SAP deficiency contributes to immune dysfunction remains incompletely understood. In this study, we found that CD4 and CD8 T cells lacking SAP had a diminished capacity to differentiate into IL-17-producing Th17 and T cytotoxic (Tc17) cells relative to wild-type lymphocytes. The use of costimulating SLAM Abs was found to augment the differentiation of IL-17-secreting effectors in wild-type but not Sh2d1a(-/-) splenic T cells under IL-17-polarizing conditions. In addition, SAP's regulation of IL-17-secreting T cells was shown to be a T cell-intrinsic role, as purified naive Sh2d1a(-/-) CD4 and CD8 T cells were inherently defective at converting into Th17 and Tc17 cells in vitro and in vivo. Furthermore, Sh2d1a(-/-) mice were protected from EAE and exhibited greatly decreased numbers of CNS-infiltrating Th17 and Tc17 effector T cells and reduced disease severity. Collectively, these results suggest that SLAM-SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo and contributes to the pathogenesis of autoimmunity in EAE.
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Kevin
authors.initials: K
authors.lastname: Tsai
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Division of Gastroenterology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; and.
authors.forename: Caixia
authors.initials: C
authors.lastname: Ma
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Division of Gastroenterology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; and.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; jpriatel@cfri.ubc.ca rtan@sidra.org.
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.affiliation: Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Department of Pathology, Sidra Medical and Research Center, Doha, Qatar jpriatel@cfri.ubc.ca rtan@sidra.org.
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D007114:Immunization; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D011956:Receptors, Cell Surface; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D015847:Interleukin-4; D007371:Interferon-gamma