Abstract
T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8–11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity.
Highlights
T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-Major histocompatibility (MHC) complex
TCR binding to the peptide MHC complex initiates the assembly of the immunological synapse between the antigen-presenting cell and the T cell by recruiting co-stimulatory molecules on both cells and clustering of the TCR [12,13,14,15,16]
Inhibitory receptors on Natural Killer (NK) cells (KIRs, CD94/NKG2A) constantly screen for MHC I expression on antigen-presenting cells (APCs) in an effort to detect downregulation of MHC I by viruses, which have evolved mechanisms to evade T cell recognition and killing [37,38,39,40]. Activating receptors, such as NKG2D, on the other hand, engage non-classical MHC I and MHC I-like molecules that are upregulated upon cellular stress or infection, such as retinoic acid early inducible gene 1 (RAE-1), Histocompatibility 60 (H-60), MHC class I chain-related gene A (MICA), B (MICB), and UL16 binding proteins (ULBPs) [41]
Summary
Major histocompatibility (MHC) Class I and II molecules are expressed on professional antigen-presenting cells (APCs), including dendritic cells (DCs) and B cells, and present peptides to the antigen receptor (TCR) on the surface of CD4+ and CD8+ T cells [1,2,3]. TCR binding to the peptide MHC (pMHC) complex initiates the assembly of the immunological synapse between the antigen-presenting cell and the T cell by recruiting co-stimulatory molecules on both cells and clustering of the TCR [12,13,14,15,16]. Allele-specific binding pockets favor certain anchor residues (e.g., P2 and P9) and provide peptide ligand specificity for polymorphic MHC I molecules of all classical haplotypes (HLA-A, -B, and -C). The preference of these pockets for certain amino acids allowed the development of algorithms to predict peptide binding to both MHC class I and II [26,27,28,29]. Sci. 2020, 21, 7561 with MHC binding predictions is the starting point for personalized T cell-based immunotherapies, such as adoptive T cell therapy [30,31,32,33,34]
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