Regulatory Roles Of Scavenger Receptor A In T Cell Mediated Immune Response And Autoimmune Hepatitis

Innate immunity comprises a sophisticated network of molecules, which recognize pathogens, and effector molecules, working together to establish a quick and efficient immune response to infectious agents. It is considered to be the first line of host by recognizing pathogen associated molecular patterns ?PAMPs? through its pattern recognition receptors such as Toll-like receptor ?TLR?, Mannose Receptor?MR?, Scavenger Receptor ?SR?, peptidoglycan recognition proteins ?PGRPs?,mannan-binding lectin ?MBL, also known as mannose-binding lectin?, assessing the level of danger, determining the nature and extend of adaptive immune response.The mechanisms of innate immunity in shaping adaptive immunity has been the focus of interest for many research groups around the world.Scavenger receptors ?SRs? represent a large family of protein molecules with diverse structures and a broad ligand-binding specificity. Scavenger receptor A?SRA?,also termed CD204 or macrophage scavenger receptor,is the prototypic member of the family and was initially identified because of its ability to bind and internalize modified low-density lipoprotein. A large body of information supports the role of SRA/CD204 in the pathogenesis of atherosclerosis and host defense through pathogen recognition and clearance. In addition, subsequent studies have also revealed other features of this multifunctional molecule. While SRA/CD204 displays a protective role in endotoxic shock, Alzheimer's disease, and hyperoxia-induced lung injury,it has been shown to contribute to the pathophysiology of cerebral ischemic injury. Moreover, germline mutations and sequence variants of SRA/CD204 gene have been reported to play a role in the development of prostate cancer albeit with ethnic-specific differences in risk estimates. SRA/CD204 is expressed primarily on phagocytic cells or antigen presenting cells ?APCs? involved in immune functions,such as dendritic cells ?DCs? and macrophages. These specialized APCs use a repertoire of pattern recognition receptors ?PRRs?, e.g., toll-like receptors ?TLRs? and SRs,to constantly sample or sense their surroundings for the presence of stress or"danger" signals ?e.g.,foreign pathogens,tissue injury,and pathology?.Effective recognition of the ligands by PRRs and initiation of host immune responses involve coordinated signaling and endocytic pathways. These professional APCs,such as DCs,are also crucial in stimulating and instructing naive T cells during the immune responses. Emerging evidence suggests that PRRs,including TLRs,Fc receptors,DEC-205 ?CD205?,DC-SIGN,and mannose receptor,play important roles in regulating the functions of DCs and maintenance of immune homeostasis as well as host defense. Indeed, early studies suggested that chemical modification of antigens for targeting to SRs increases the immunogenicity of these antigens. Several SRs, including SRA/CD204, have been reported to mediate uptake of stress proteins and their associated antigens. However, the mechanisms of SRA/CD204 action in antigen presentation and adaptive immunity remain poorly defined.Despite the implication of SRA/CD204 in ligand binding and internalization,we recently made an unexpected discovery showing that SRA/CD204 was capable of attenuating vaccine response and antitumor immunity. That lack of SRA/CD204 markedly promoted vaccine-elicited tumor-protective immunity may be attributed to the enhanced DC functions and activation of cytotoxic CD8+ T lymphocytes.Downregulation of the ability of DC to stimulate CD8+ T cells and tumor immunity by SRA/CD204 has been reported in the context of the cross-presentation of soluble antigens as well as cell-associated antigen. However, it is not clear whether the SRA/CD204 also influences DC-mediated activation of antigen-specific CD4+ T cell response.The present study aimed to determine the regulatory roles of SRA/CD204 on adaptive immunity, especially its regulatory roles on T cell. We investigated whether SRA/CD204 have an effect on proliferative responses and cytokine secretion of purified T cells and the mechanisms of its function. Our results uncover an essential mechanism of SRA/CD204-mediated protection of liver damage,which provides insight into liver pathophysiology and offers new opportunities to develop future therapeutic strategies.Part ? Suppression of antigen-specific CD4+ T cell activation by SRA/CD204 through reducing the immunostimulatory capability of antigen-presenting cell Pattern recognition scavenger receptor SRA/CD204, primarily expressed on specialized APCs, including 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 naive OT-? 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-cellstimulating activity in vitro, which was independent of the classical endocytic property of the SRA/CD204. Additionally, absence of SRA/CD204 resulted in significantly elevated IL-12 p35 expression in DCs upon CD40 ligation plus interferon gamma ?IFN-?? 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-y. Furthermore, splenocytes from the generated SRA-/- OT-? mice showed heightened proliferation upon stimulation with OVA protein or MHC-II-rest:ricted OVA323₃39 peptide compared with cells from the SRA+/+ OT-? 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.Part ? SRA/CD204 co-stimulation blocks activation of T cells by inhibiting T cell receptor signalingNaive T cells triggered by antigen-presenting cells expressing a membrane-bound form of SRA/CD204 or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant SRA/CD204 had reduced activation and proliferation. A monoclonal antibody that blocks binding of SRA/CD204 to T cells enhances T cell proliferation in vitro. Recombinant SRA/CD204 protein binds to activated but not naive T cells. SRA/CD204 is primarily expressed on antigen presenting cells, and its expression is highly regulated during antigen specific T cell activation in vivo and in vitro. Triggering of proximal T cell receptor signaling during T cell priming interfered with SRA/CD204 by inhibiting the tyrosine protein phosphorylation of ?-chain-associated protein of 70 kD and linker for the activation of T cells as well as nuclear factor kappa B. Subsequently,Ca2+ mobilization was strongly reduced, leading to impaired cytokine secretion. This study identifies a novel negative regulator of T cell activation and further reveals complex costimulatory regulation of immune responses.Part ? SRA/CD204 restrains T cell activation and protects against concanavalin A-induced hepatic injuryNegative feedback immune mechanisms are essential for maintenance of hepatic homeostasis and prevention of immune-mediated liver injury. We show here that scavenger receptor A ?SRA/CD204?, a pattern recognition molecule, is highly upregulated in the livers of patients with autoimmune or viral hepatitis, and of mice during concanavalin A ?Con A?-induced hepatitis ?CIH?. Strikingly,ablation of SRA/CD204 strongly sensitizes mice to Con A-induced acute liver injury, which depends on excessive production of IFN-? and is associated with heightened activation of T cells. Increased liver expression of SRA/CD204 primarily occurs in mobilized hepatic myeloid cells during CIH, including CDllb+Gr-1+ cells.Mechanistic studies establish that SRA/CD204 on these cells functions as a negative regulator limiting T cell activity and cytokine production. The critical role of SRA/CD204 during CIH was further confirmed by adoptive transfer of SRA+/+hepatic mononuclear cells or administration of lentivirus-expressing SRA/CD204,which effectively ameliorated Con A-induced hepatic damage. We also report for the first time that CIH in mice was associated with the release of soluble SRA/CD204 that displayed direct T cell inhibitory effects. Furthermore, treatment with soluble SRA/CD204 is capable of mitigating Con A-induced liver pathology and damage.Our findings demonstrate an unexpected role of SRA/CD204 in attenuation of Con A-induced, T cell-mediated hepatic injury. We propose that SRA/CD204 serves as an important negative feedback mechanism in liver immune homeostasis, and may be exploited for therapeutic treatment of inflammatory liver diseases.In summary, results above have showed that SRA/CD204 suppressed proliferation and .activation of naive T cells. Inhibition was associated with a decreased production of cytokines. Acquire direct clue that MBL can interact with T cell. Our results uncover an essential mechanism of SRA/CD204-mediated protection of liver damage, which provides insight into liver pathophysiology and offers new opportunities to develop future therapeutic strategies. Our findings support the notion that SRA/CD204 on APCs as well as soluble SRA/CD204 function as an immunosuppressive molecule capable of restricting T cell activation and may serve as a basis for the rational design of novel strategies targeting SRA/CD204 to achieve improved immunotherapeutic efficacy against cancer and other diseases.