A structural voyage toward an understanding of the MHC‐I‐restricted immune response: lessons learned and much to be learned

Abstract

T cells that express clonally distributed αβ T-cell receptors (TCRs) corecognize antigenic peptides (p) bound to major histocompatibility complex class I (MHC-I) and class II molecules (MHC-II). Extensive human leukocyte antigen (HLA) polymorphism enables HLA molecules from different haplotypes to capture an array of self- and microbe-derived peptide antigens that is fundamental to adaptive immunity. T cells developing in the thymus are selected for weak binding to self-peptide-HLA complexes generating a vast repertoire of clonally distinct T cells in the periphery. Indeed, diversity within germline loci and the finally assembled TCR genes, coupled with inherent TCR cross-reactivity, enables CD8(+) T cells to survey the multitude of pHLA-I landscapes. Precisely how does the TCR ligate to pHLA-I, and how does knowledge of the detailed structural interactions inform immunobiology? A recent number of our structural studies concerning the TCR-pMHC-I axis, alongside others in the field, have provided insight into HLA-I polymorphism, pMHC-I flexibility, TCR bias, TCR polymorphism, maintenance of self-tolerance, T-cell cross-reactivity, and alloreactivity. Collectively, the data also provide an opportunity to address the structural correlates of MHC-I restriction. Here, we provide our perspective concerning these advances in the field. Although much key information has been gleaned, the structural data show that some of the key concepts surrounding the TCR-pMHC-I interaction remain controversial and unresolved.

An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant

“…R ) was similar (K deq of 6.6 mM) (Supplemental Fig. 1B (32). In contrast, the affinity of DD31 TCR for the P4 K .…”

“…Conversely, P8-E also interacting, by similar bonds, with the Arg 109 b was less stranded than P7-D and so would be more disposed to accommodate variation. Previous studies on TCR-pHLA cocomplexes suggest that in general, most TCRs usually contact only one or two solventexposed residues to achieve specificity (32,35). For example, despite an array of solvent-exposed residues (P4, P6, P7, or P8) in the EBV epitope HLA-B*0801/FLR, its recognition by LC13 TCR is dependent on P7-Y, which resides within the bulged and exposed region of the peptide (41).…”

Increased Diversity of the HLA-B40 Ligandome by the Presentation of Peptides Phosphorylated at Their Main Anchor Residue

“…Most of these polymorphisms are located within the ␣1 and ␣2 domains of the heavy chain and modulate the peptide binding preferences of each allotype (8). It is thought that the great diversity of HLA class I allotypes, and of their associated ligandomes, is an adaptation to guarantee immunity against intracellular pathogens (6). In this regard, the existence of a large number of different class I molecules capable of presenting diverse peptidomes hampers immune evasion by means of viral genetic mutation.…”

“…The MHC, known as the human leukocyte antigen (HLA) system in humans, is the most polymorphic region in the entire genome (6). In particular, the IMGT/HLA database (7) currently contains about 7000 allele sequences that encode more than 5000 different human class I antigens.…”

Analysis of Relationships between Peptide/MHC Structural Features and Naive T Cell Frequency in Humans

“…In some cases, changes in the peptide conformation are also observed upon TCR binding (45). As the affinity of the TCR for a cognate pMHC is rather moderate [i.e., in by guest on May 11, 2018 http://www.jimmunol.org/ the 1-100 mM range (46,47)], the energetic cost of stabilizing part of the TCR-pMHC interface can represent a significant contribution to the global free energy of binding. Therefore one can expect that a less mobile peptide could favor TCR binding, as it would reduce the entropic cost of further stabilizing the peptide.…”