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

Abstract

Heat shock proteins (HSP) can interact with a wide variety of peptides and the resulting HSP:peptide complexes are known to be highly immunogenic. The ability of HSP:peptide complexes to elicit CD8 + T cell responses by cross-presentation of exogenous antigen via MHC class I is well known. In contrast, their role in the activation of CD4 + T cells is less clearly defined, although several recent studies in mice and T cell lines suggest an involvement of HSP in the presentation of antigenic peptides via MHC class II. In this study we have investigated the potential of antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to the human stress-inducible Hsp70 to enhance activation and proliferation of human memory CD4 + T cells. Hsp70:peptide complexes were found to amplify the proliferation of antigen-specific CD4 + T cells as confirmed by HLA-DR tetramer staining. Complex formation of the antigenic peptide with Hsp70 was absolutely required to elicit an antigen-specific amplification. This effect was most pronounced at low doses of antigen and decreasing APC/CD4 + T cell ratios. Taken together, we show the potential of Hsp70 to enhance antigen-specific CD4 + T cell proliferation and to increase the immunogenicity of presented peptides in human CD4 + T cells.

A heat shock protein gene (Hsp70.1) is critically involved in the generation of the immune response to myelin antigen

“…While most data on the contribution of hsp-peptide interactions have addressed immune responses involving MHC class Idependent pathways [21][22][23][24], more recent results from this [25], and other [26][27][28][29] laboratories indicate that hsp are also capable of participating in antigen presentation in MHC class II-dependent pathways. In this respect, hsp70 is a major hsp implicated in the formation of immunogenic complexes and the facilitation of MHC presentation.…”

70‐kDa heat shock proteins: Specific interactions with HLA‐DR molecules and their peptide fragments

“…In our experiments testing affinities of HLA-DR-derived peptide fragments as well as other peptide sequences, HSP70 affinities showed an optimum at neutral pH and affinities were reduced at lower pH. Therefore, HSP70-bound peptides might be released at the lower pH of the late endosomal compartments and transferred onto MHC class II molecules involving direct HSP70:HLA-DR interaction, resulting in enhanced antigen presentation and activation of antigen-specific CD4 + T cells, as we have previously demonstrated [11]. The increased HSP70 affinity of HLA-DR molecules at slightly acidic pH values also argues for this hypothesis.…”

“…The direct and specific binding of HSP70 molecules to HLA-DR might be of importance for the enhanced activation of human antigen-specific T cells with HSPchaperoned peptides, particularly with low doses of antigen or reduced APC numbers [11]. In a possible scenario, HSP70 molecules might serve as scanner and carrier for (auto-)antigenic peptides: Extracellular HSP:peptide complexes, released by necrotic cells [32] can be taken up by APC via specific receptors (reviewed in [33]) and thus reach endocytic and MHC class II loading compartments [15].…”

“…HSP were shown to be involved in activating APC via different signaling pathways [1,2] and they have been identified as immunological targets inducing T cell responses with immunomodulatory effects [3][4][5][6]. Additionally, HSP-chaperoned antigenic peptides can be presented via MHC class I and II molecules and thus induce enhanced activation of antigen-specific CTL and CD4 + T cells [7][8][9][10][11].…”

T cell recognition of naturally presented epitopes of self-heat shock protein 70

“…One of the main functions of HSPs is to chaperone other proteins. HSP-chaperoned antigenic peptides can be presented via MHC class I and II molecules inducing enhanced activation of antigen-specific CTL and CD4+ T cells (Haug et al 2005;Mycko et al 2004;Singh-Jasuja et al 2000;Tobian et al 2004;Udono and Srivastava 1993). Furthermore, HSPs themselves are involved in activating the innate arm of the immune system via different signaling pathways (Asea et al 2000;Vabulas et al 2002).…”