Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T‐cell activation

Abstract

IntroductionSuccessful vaccination depends on activation of CD8 + and CD4 + T-cell responses by presentation of antigenic peptides in the context of major histocompatibility complex class I (MHCI) and II Correspondence: Dr. Tone F. Gregers e-mail: t.f.gregers@ibv.uio.no (MHCII) molecules, respectively. The processing and subsequent presentation of antigenic peptides by MHCI or MHCII molecules on the surface of antigen presenting cells (APCs) requires a coordinated action of different accessory molecules and dedicated chaperones. Targeting of Ags to these pathways that * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 774-784 Immunomodulation 775 improve presentation to T cells, would therefore be expected to potentiate vaccine strategies. MHCII interacts with the dedicated chaperone invariant chain (Ii) in the ER. Ii contains sorting signals within its cytoplasmic tail, which mediate trafficking of Ii-MHCII to proteolytic endosomal compartments where Ag loading takes place [1]. In the endosomal pathway Ii is sequentially degraded, leaving a residual CLIP in the peptide-binding groove of MHCII, which is exchanged by specific antigenic peptides by the action of HLA-DM.Indeed, Ags targeted to the endosomal pathway for loading onto MHCII have successfully been shown to activate CD4 + T-cell responses. Ag targeting has been achieved using signals associated with lysosomal proteins, such as lysosomal-associated membrane protein 1 [2] or other lysosomal hydrolases [3], by direct coupling of the Ag to full-length Ii, or to Ii containing the endosomal localization signal only [4,5]. Finally, genetic exchange of the CLIP sequence with antigenic epitopes was demonstrated to be highly efficient for loading of MHCII and CD4 + T-cell activation [6]. In fact, this strategy has proven to be superior compared to peptide loading for priming of CD4 + T cells and tumor protection in vivo [7, 8].Loading of MHCI molecules for vaccine purposes has commonly been achieved by exogenous pulsing of APCs with synthetic peptides in vitro. This approach is limited by rapid degradation of peptides, the risk of inducing T-cell tolerance [9], and the possibility for the formation of cryptic epitopes leading to imprecise tumor targeting [10]. Another alternative is Ag delivery by mRNA [11] or DNA [12], relying on protein production and proteasomal degradation to generate high peptide concentrations in the cytosol of the APC. Peptides are subsequently translocated into the ER by transporters associated with Ag processing (TAP), and loaded onto MHCI [11]. However, vaccination strategies that are independent of proteasomal degradation might represent an advantage in several contexts. Some tumor Ags are processed more efficiently by the immunoproteasomes of dendritic cells (DCs) than by the standard proteasomes present in the majority of other cells, whereas for others the situation is vice versa [13,14]. Moreover, the combination of immunotherapy with certain...

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…The li, a 33 kDa polypeptide, is involved in the stabilization and proper folding of HLA class II antigens as well as in the prevention of binding cellular peptides on HLA class II antigens, while it could also serve as vehicle to load antigenic peptides on MHC class I molecules. 15 In addition, the li facilitates the export of HLA class II molecules from the ER and is responsible for directing the HLA class II complexes into specialized endosomal/lysosomal antigen loading compartments, termed MHC class II containing compartment (MIIC). Here, the li is proteolytically degraded by cathepsin into the 14 amino acid long class II-associated invariant chain peptide (CLIP) occupying the HLA class II peptide-binding groove.…”

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

“…The cloning strategy is shown in Figure 1A. 21 Briefly, cDNA was tagged with a poly-C tail using a terminal transferase reaction. The V regions were amplified using a common poly-GI forward primer (pGI: 59-CACCGGGIIGGGIIGGGII-39) and 2 different sets of human constant region-specific reverse primers (pC1 and pC2: pCa1, 59-AGTCAGATTTG TTGCTCCAGGCC-39; pCb1, 59-TTCACCCACCAGCTCAGCTCC-39; pCa2, 59-ATACGCGTTCTCTCAGCTGGTACACGG-39; pCb2, 59-ATACGCG TAGATCTCTGCTTCTGATGGC-39).…”

The efficacy of chimeric vaccines constructed with PEP-1 and Ii-Key linking to a hybrid epitope from heterologous viruses

“…Kim et al [23] found that the combination of CIITA DNA with Ii-PADRE DNA (Ii linked to the pan-HLA-DR-reactive epitope) and calreticulin (CRT)/E6 (co-administration of DNAencoding CRT linked to human papillomavirus 16 E6 Ag) enhanced E6-specific CD8þ T cell immune responses and represents a potentially effective method to combat tumours in clinical settings. CLIP-replaced Ii efficiently activated Ag-specific CD8þ T cells independent of the classical MHC I peptide-loading machinery [24]. Ii-Key, the core fragment of Ii, has been shown to facilitate direct loading of MHC class II epitopes onto the peptidebinding groove [6,25,26].…”