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 OVA323–339 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.
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Abbreviations
- PRR:
-
Pattern recognition receptor
- SRA:
-
Scavenger receptor A
- DC:
-
Dendritic cell
- MPL:
-
Monophosphoryl lipid A
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Acknowledgments
This work was supported by the National Cancer Institute (NCI) Grants CA129111, CA154708, and CA099326, American Cancer Society Scholarship RSG-08-187-01-LIB, Harrison Endowed Scholarship, and NCI Cancer Center Support Grants to Massey Cancer Center.
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H.Y., D.Z., X.Y., and F.H., performed experiments and analyzed data. M.M., Z.C., and J.S. contributed to data analyses. X-Y.W. designed and supervised the research. X-Y.W., H.Y., and D.Z. wrote the manuscript.
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The authors declare no conflict of interests related to this study.
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H. Yi and D. Zuo contributed equally to this work.
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Yi, H., Zuo, D., Yu, X. et al. Suppression of antigen-specific CD4+ T cell activation by SRA/CD204 through reducing the immunostimulatory capability of antigen-presenting cell. J Mol Med 90, 413–426 (2012). https://doi.org/10.1007/s00109-011-0828-1
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DOI: https://doi.org/10.1007/s00109-011-0828-1