title: Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity.
abstract: Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (TFH) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in TFHcell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient TFHcells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP.
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Shasha
authors.identifier: 0000-0002-6067-3966
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Chenxu
authors.initials: C
authors.lastname: Cai
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Zehua
authors.identifier: 0000-0001-6342-3324
authors.initials: Z
authors.lastname: Li
authors.affiliation: Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
authors.forename: Guangao
authors.initials: G
authors.lastname: Liu
authors.affiliation: Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
authors.forename: Yuande
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136.
authors.forename: Marzenna
authors.identifier: 0000-0001-5237-8732
authors.initials: M
authors.lastname: Blonska
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Dan
authors.identifier: 0000-0002-3215-8262
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
authors.forename: Meixiang
authors.initials: M
authors.lastname: Yang
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China dongzj@biomed.tsinghua.edu.cn.
authors.forename: Zhongjun
authors.identifier: 0000-0002-2673-4200
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D056724:Immunity, Humoral; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D055611:Natural Killer T-Cells / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000502:physiology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D015398:Signal Transduction / Q000502:physiology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein / Q000502:physiology; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000502:physiology*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1 / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; D053468:CARD Signaling Adaptor Proteins; D051741:Kruppel-Like Transcription Factors; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C496467:Card11 protein, mouse; C000604062:Slamf1 protein, mouse; C513267:Zbtb16 protein, mouse; C000604063:Slamf6 protein, mouse