Keywords

1 Introduction

Mammals possess two types of immune responses, that is, innate immunity and acquired immunity. Innate immunity is activated against broad rages of pathogens nonspecifically by recognizing pathogen patterns. On the other hand, acquired immunity responds specifically to invaded pathogens. To recognize pathogens in the acquired immune response, dendritic cells (DCs) take pathogens by phagocytosis, and pathogen-derived proteins are fragmented to peptides by intracellular proteases. As a result, the antigen peptides bind to major histocompatibility complex class I or class II molecules (MHC-I or MHC-II) inside the cells, and the antigen-bound MHCs are presented on the cell surface. Moreover, DCs also have a mechanism to present cytoplasmic antigens by MHCs. Many researches have been conducted to elucidate the transport pathways of the antigens to both MHC-I and MHC-II. Recently, the involvement of HSP family proteins in these pathways has also been found.

1.1 Mechanisms of Antigen Presentation by Dendritic Cells

In the acquired immune response, pathogen-derived antigen peptides are presented from DCs to T cells using cell surface MHC molecules (MHC-I or MHC-II). MHC-I presents antigens to CD8+ T cells, also called cytotoxic T lymphocytes (CTLs), whereas MHC-II presents antigens to CD4+ T cells, also called helper T cells. Classically, MHC-I was thought to bind and present intracellular cytoplasmic antigens such as an infected virus-derived peptide. Cytoplasmic antigens are processed to peptides by proteasomes, and the generated peptides enter the ER through a peptide transporter, TAP, where the peptides bind to MHC-I [3]. DCs also present antigens that are taken up from outside the cells by MHC-I. This mechanism is called cross-presentation and is necessary for the activation of CTLs to kill virus-infected cells and tumor cells [3, 11]. There are two pathways for the antigen cross-presentation by MHC-I. One is a cytoplasmic pathway, which is TAP-dependent, and antigens are once transferred in the cytosol and internalized in the ER through TAP. The other is the vacuolar pathway, which is TAP independent. The antigens bind directly to MHC-I within the phagosomes or the endosomes. ([2, 11]; Fig. 1).

Fig. 1
figure 1

Role of HSP in antigen presentation. Dendritic cells present antigen through the MHC-I or MHC-II pathway. HSP assists in the antigen presentation in various ways. In the MHC-I pathway, extracellular HSP90 assists in the uptake of exogenous antigens into the cells. In the cytoplasm, HSP90 assists in the transfer of antigen from the phagosome to the cytoplasm. In the MHC-II pathway, HSP70 binds to the antigen in the cytoplasm and assists in the translocation of MHC-II to MIIC by chaperone-mediated autophagy. HSC70 also assists in the transfer of cytoplasmic antigens into autophagosomes for macroautophagy

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MHC-II binds and presents exogenous antigens such as extracellular bacterium-derived proteins. The antigens are taken into cells by uptake mechanisms such as phagocytosis or endocytosis and then transported to the intracellular vesicle, MHC-II compartment (MIIC), where MHC-II is localized [17]. Furthermore, MHC-II also presents intracellular antigens through another mechanism by which cytoplasmic antigens enter MIIC by autophagy. This mechanism is thought to be important for the presentation of cytoplasmic pathogens-derived antigens [18]. This mechanism of cytoplasmic antigen presentation is also required for the presentation of self-antigens to CD4+ T cells to induce immune tolerance [6, 15].

1.2 Roles of HSP in Antigen Presentation by MHC-I

HSP has been reported to regulate antigen presentation by binding to antigen proteins as a molecular chaperone protein. The role of HSP in MHC-I-mediated antigen presentation has been well studied. Extracellular HSP90 binds to exogenous antigens outside the cell and assists in the uptake of the antigen to the cross-presentation pathway. It has been observed that extracellular HSP90-ovalbumin (OVA) protein complexes are transported to the early endosome and enter the cross-presentation pathway [19]. Since the internalized HSP90-OVA complex is colocalized with proteasomes in the cytosol, HSP90 could be involved in the TAP-dependent cross-presentation pathway and play a key role in promoting the transition of the antigen from the endosomes to the cytosol [16]. HSP90 has been reported to assist in the cross-presentation of tumor-derived antigens. However, in this case, the cross-presentation pathway has shown to be a TAP-independent vacuolar pathway [14]. The cytoplasmic HSP90 is also involved in cross-presentation. HSP90α was shown to be required for the cytoplasmic transition of antigens by using HSP90 inhibitors. In addition, cross-presentation was reduced in HSP90α-deficient DCs, although the presentation of cytosolic antigens by MHC-I was not affected [7, 9, 10, 20]. HSP other than HSP90 is also involved in cross-presentation. Hsp70 and gp96 (also known as Grp94 or Hsp90B) were reported to assist in the uptaking of exogenous antigens [1].

1.3 Roles of HSP in Antigen Presentation by MHC-II

The role of HSP in antigen presentation by MHC-II is not as well understood as MHC-I. HSP90 has been reported not to promote MHC-II-mediated antigen presentation of exogenous antigens derived from OVA protein [16]. On the other hand, it has also been reported that MHC-II-mediated presentation of extracellular glutamate decarboxylase (GAD)-derived peptides was promoted by HSP90 [8]. Therefore, the role of extracellular HSP90 on MHC-II-mediated antigen presentation may depend on the antigen proteins.

The role of cytoplasmic HSP in MHC-II-mediated antigen presentation has also been reported. One of the roles of cytoplasmic HSC70 is chaperone-mediated autophagy (CMA). In CMA, proteins are transported into the autophagosomes by a lysosomal transmembrane protein Lamp2a [12]. HSC70 assists in the association of the antigens to Lamp2a during CMA [21]. Several endogenous antigens are reported to be transferred into the autophagosome by CMA and presented by MHC-II [4, 21]. HSP70 has also been reported to involve in macroautophagy-mediated antigen presentation by MHC-II. HSC70 assists in the transition of proteins into autophagosomes [5, 13].

2 Conclusions

Many studies have revealed the roles of HSPs in antigen presentation. In particular, the functions of HSP90 in the MHC-I pathway and the functions of HSP70 in the MHC-II pathway are being elucidated. However, several unsolved questions have still remained. For example, does the same mechanism function in all antigen-presenting cells? Is there specificity for antigen proteins in the HSPs? In addition, the involvement of the other HSPs in antigen presentation is still unclear. Since acquired immunity is important for the elimination of pathogens and tumors, antigen presentation should be a promising target for immunotherapy for infectious diseases and cancers. HSPs may be a potential target for manipulation of antigen presentation.