Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses.
CD100/Sema4D belongs to the semaphorin family, factors known to act as repulsive cues for axons during neuronal development. Mouse CD100 plays a crucial role in both humoral and cellular immunity through ligation of the lymphocyte receptor, CD72. It remains controversial, however, whether human CD100 can function through human CD72 in a manner similar to mouse CD100. To determine the function of human CD100, we generated a recombinant soluble human CD100 protein comprised of the extracellular region of human CD100 fused to the human IgG1 Fc region (hCD100-Fc). hCD100-Fc specifically binds to cells expressing human CD72. As observed previously in the mouse, hCD100-Fc induces the tyrosine dephosphorylation of human CD72, leading to the dissociation of SHP-1 from the CD72 cytoplasmic tail. Consistent with findings for mouse CD100, hCD100-Fc exerts a co-stimulatory effect on B cells and dendritic cells that are stimulated with anti-CD40 mAb. Furthermore, both hCD100-Fc and anti-human CD72 agonistic mAb induce the production of the pro-inflammatory cytokines tumor necrosis factor-alpha, IL-6 and IL-8, even in the absence of anti-CD40 mAb. Collectively, our findings not only demonstrate that human CD100, interacting with human CD72, can function as a ligand in a manner similar to mouse CD100, but also suggest the involvement of human CD100 in inflammatory responses.
Ishida
Isao
I
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Kumanogoh
Atsushi
A
Suzuki
Kazuhiro
K
Akahani
Shiro
S
Noda
Kazuhiro
K
Kikutani
Hitoshi
H
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D016466:CHO Cells; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006224:Cricetinae; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D018664:Interleukin-12 / Q000032:analysis / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism; D009419:Nerve Tissue Proteins; D014066:Palatine Tonsil / Q000166:cytology; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C093224:CD100 antigen; D019013:CD40 Antigens; C064228:CD72 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D039961:Semaphorins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse