Mechanistic diversity in MHC class I antigen recognition

Abstract

Throughout its evolution, the human immune system has developed a plethora of strategies to diversify the antigenic peptide sequences that can be targeted by the CD8+ T cell response against pathogens and aberrations of self. Here we provide a general overview of the mechanisms that lead to the diversity of antigens presented by MHC class I complexes and their recognition by CD8+ T cells, together with a more detailed analysis of recent progress in two important areas that are highly controversial: the prevalence and immunological relevance of unconventional antigen peptides; and cross-recognition of antigenic peptides by the T cell receptors of CD8+ T cells.

Keywords: MHC class I; T cells; TCR; antigens; spliced peptides.

Figure 1.. Key steps in the diversity of peptides presented via the MHC-I antigen processing and presentation (APP) pathway.

The MHC-I APP pathway consists of a sequence of steps: (a) peptide generation mostly by proteasomes; (b) peptide trimming by aminopeptidases in the cytosol (e.g. TPP2) and in the ER (e.g. ERAP1); (c) peptide transport into the ER, mostly via TAP; (d) assembly of the MHC-I-peptide-PLC in the ER; (e) MHC-I-peptide presentation at the cell surface. All these steps modulate MHC-I immunopeptidome diversity.

Figure 2.. Proteasome isoforms.

(A) The human 20S proteasome is shown based on the structure generated by Schrader et al. [30]. The chains B, C, H, I, J, Q, R, S, Y and Z are hidden from the structure to show the inner proteasome cavities with the central chamber and its two antechambers. The α and β subunits are coloured in grey and blue, respectively. The β2 subunit is shown in pink with its active site Thr₁ in red, as an example of a catalytic subunit. (B) Proteasome isoforms. 20S proteasomes can be present in many isoforms, which vary on the base of their catalytic subunits. 20S proteasomes can binds to several regulatory complexes, which change both the conformation and the activity of the 20S proteasome core.

Figure 3.. Proteasome-catalysed peptide splicing (PCPS).

(A) Spliced peptides can be formed by: (i) cis-PCPS, i.e. when the two splice-reactants derive from the same protein. The ligation of the splice-reactants can occur in normal order, i.e. following the orientation from N- to C-terminus of the parental protein (forward cis-PCPS), or in the reverse order (reverse cis-PCPS); (ii) trans-PCPS, when the two splice-reactants originate from two distinct proteins. (B) Transpeptidation. Proteasome's catalytic Thr₁ breaks the peptide bond of the residue (P1) of the protein - thereby forming an acyl-enzyme intermediate with the N-terminal splice-reactant, and releasing the C-terminal peptide fragment. The acyl-enzyme intermediate can then interact with another peptide fragment (the C-terminal splice-reactant) and form a new peptide bond between the P1 residue of the N-terminal splice-reactant and the residue P1′ of the C-terminal splice-reactant.

Figure 4.. Structure of a CD8⁺ TCR.

(A) A CD8⁺ TCR bound to a cognate MHC-I-peptide complex. The TCR is shown in blue (α chain) and cyan (β chain) with the constant (C) and variable (V) regions annotated. The peptide is shown in red and the MHC-I in green with the α-helices (α1 through α3) and β2 microglobulin (β2M) annotated. (B) Looking more closely at the variable region of the TCR reveals the six complementarity determining regions (CDRs) at the interface with the MHC-I-peptide complex. Note the central position of the CDR3s on both the α and β chains; these are the CDRs most associated with peptide contacts.

Figure 5.. Structural mechanisms of T cell cross-reactivity.

(A) Cross-reactivity can be facilitated by the significant conformational plasticity of the TCR, particularly in the CDR loops. Here a TCR (blue) changes conformation to bind different MHC-I-peptide complexes. (B) Similarly, the MHC-I-peptide complex can undergo conformational changes that promote binding with different TCRs. (C) Variable TCR docking angles can alter the interface and allow for binding a broader range of MHC-I-peptide complexes. TCR docking angles vary substantially in the vertical (TCR tilt) and horizontal (TCR twist) planes. (D) Different peptides can bind with the same TCRs by presenting very similar physicochemical surfaces at the interface. Here peptides are shown substituting arginine (R) residues for lysine (K) residues, which conserve physicochemical features such as positive charge and polarity. (E) TCR-MHC-I-peptide binding is an interplay of multiple factors including shape complementarities, hydrogen bonds, salt bridges, and van der Waals interactions. This confederation of forces includes some redundancy and often binding can be achieved with a subset of the factors. This allows binding to be resilient to substitutions in peptide sequences.