title: Suppression of antigen-specific CD4+ T cell activation by SRA/CD204 through reducing the immunostimulatory capability of antigen-presenting cell.
abstract: Pattern recognition scavenger receptor SRA/CD204, primarily expressed on specialized antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages, has been implicated in multiple physiological and pathological processes, including atherosclerosis, Alzheimer's disease, endotoxic shock, host defense, and cancer development. SRA/CD204 was also recently shown to function as an attenuator of vaccine response and antitumor immunity. Here, we, for the first time, report that SRA/CD204 knockout (SRA(-/-)) mice developed a more robust CD4(+) T cell response than wild-type mice after ovalbumin immunization. Splenic DCs from the immunized SRA(-/-) mice were much more efficient than those from WT mice in stimulating naïve OT-II cells, indicating that the suppressive activity of SRA/CD204 is mediated by DCs. Strikingly, antigen-exposed SRA(-/-) DCs with or without lipopolysaccharide treatment exhibited increased T-cell-stimulating activity in vitro, which was independent of the classical endocytic property of the SRA/CD204. Additionally, absence of SRA/CD204 resulted in significantly elevated IL12p35 expression in DCs upon CD40 ligation plus interferon gamma (IFN-γ) stimulation. Molecular studies reveal that SRA/CD204 inhibited the activation of STAT1, mitogen activated protein kinase p38, and nuclear factor-kappa B signaling activation in DCs treated with anti-CD40 antibodies and IFN-γ. Furthermore, splenocytes from the generated SRA(-/-) OT-II mice showed heightened proliferation upon stimulation with OVA protein or MHC-II-restricted OVA(323-339) peptide compared with cells from the SRA(+/+) OT-II mice. These results not only establish a new role of SRA/CD204 in limiting the intrinsic immunogenicity of APCs and CD4(+) T cell activation but also provide additional insights into the molecular mechanisms involved in the immune suppression by this molecule.
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.forename: Daming
authors.initials: D
authors.lastname: Zuo
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Chen
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D055786:Gene Knockout Techniques; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology*; D051117:Scavenger Receptors, Class A / Q000235:genetics* / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D007371:Interferon-gamma; D010047:Ovalbumin
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