title: SAP-regulated T Cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions.
abstract: The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell-cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is required for stable cognate T-B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T-B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108-CD3ζ interactions. Constitutively associated with Src homology 2 domain-containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100-200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell-cell interactions, Ly108-CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108-CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T-B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell-APC interactions.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Coco
authors.initials: C
authors.lastname: Chu
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Xinya
authors.initials: X
authors.lastname: Ni
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Junxia
authors.initials: J
authors.lastname: Cao
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Wan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Laboratory of Tumor Immunology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China; and.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China; and.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wei
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing 100021, People's Republic of China.
authors.forename: Yuanwu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing 100021, People's Republic of China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Longyan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; qihai@tsinghua.edu.cn.
authors.forename: Hai
authors.initials: H
authors.lastname: Qi
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D018858:Germinal Center / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000276:immunology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D000950:Antigens, Ly; D017252:CD3 Complex; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D055765:Shc Signaling Adaptor Proteins; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C121704:CD3 antigen, zeta chain; C499569:Sh2d1a protein, mouse; C000604063:Slamf6 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family