Inducible Heat Shock Protein 70 Promotes Myelin Autoantigen Presentation by the HLA Class II

Abstract

In this study, we investigated the role of the inducible form of heat shock protein 70 (hsp70) in the presentation of the major putative autoantigen in multiple sclerosis, myelin basic protein (MBP), in the context of appropriate MHC class II. By coimmunoprecipitation, we found that MBP is associated with hsp70 in APC in an ATP/ADP-dependent manner. Additionally, using confocal microscopy, hsp70 was detected in the endocytic pathway of APC, where it colocalized with MBP and HLA-DR. The immunodominant epitopes of MBP 85–99 and 80–99 were shown to bind selectively and specifically to hsp70 by surface plasmon resonance. The functional significance of MBP interaction with hsp70 was demonstrated by the detection of enhanced responses of an MBP-specific T cell hybridoma to MBP and MBP 80–99 with increasing levels of hsp70 and reduced responses when hsp70 expression was diminished within APC-expressing DRA*0101, DRB1*1501 (DR1501). However, when MBP 85–99 was used as the stimulus, T cell hybridoma responses were not enhanced by hsp70 overexpression within APC, suggesting that hsp70 contributes to Ag processing rather than Ag presentation. The importance of a direct association between MBP and hsp70 in the presentation pathways was demonstrated by enhanced efficacy of MBP presentation by APC transfected with a plasmid vector encoding a fusion hsp70-MBP protein. This is the first report on the involvement of self-inducible hsp70 in MHC class II-dependent autoantigen processing by APC. It implicates that aberrant self hsp expression may lead to the enhancement/modulation of autoimmune responses.

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

“…Although the premise that HSPA conveys chaperoned peptides directly to the TAP complex is appealing, further detailed investigations are needed. HSPA1A (Mycko et al 2004) as well as HSPA8 (Panjwani et al 1999;Zhou et al 2005) have also been reported to enhance HLA class II antigen presentation and to localise in MIIC. Recently, different HSPs such as HSPC and CCT have been demonstrated to chaperone postproteasomal antigenic intermediates for the HLA class I presentation pathway, indicating its role in the early steps of antigen presentation (Callahan et al 2008;Shastri 2003, 2006).…”

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

“…In a murine model, gp96:peptide complexes facilitated the in vivo presentation of an MHC class II-restricted epitope, but the secretion of effector cytokines by the CD4 + T cells could not be detected [16]. Furthermore, an involvement of self-inducible Hsp70 in MHC class II-dependent autoantigen processing was reported by Mycko et al [17], and recent data indicate that bacterial HSP70 facilitates the processing and presentation of antigenic peptides by MHC class II [18]. However, most of these studies have been done in murine systems or with human T cell clones.…”

“…Our results confirm and extend, in a human antigen-specific setting, previous results in the murine system which demonstrated an enhanced immunogenicity of MHC class IIrestricted peptides complexed with HSP. Given the different associations of HSP and autoimmunity [17,[23][24][25], we postulate the hypothesis that the presence of HSP, e.g. after cell death, might be involved in the initiation of autoimmunity by facilitating an immune reaction to a possible autoantigenic peptide at concentrations where peptide without HSP would not be immunogenic at all.…”

Mycobacterium tuberculosisHeat Shock Fusion Protein Enhances Class I MHC Cross-Processing and -Presentation by B Lymphocytes

“…Dendritic cells and macrophages process exogenous HSP: peptide complexes by alternate MHC-I Ag processing (cross-processing) mechanisms, resulting in cross-presentation of exogenous HSP-chaperoned peptides to CD8 ϩ T cells (5,15,16). Bacterial and mammalian host HSPs may also contribute to MHC-II Ag processing (17)(18)(19).…”