International Journal of Molecular Sciences Review TCR Recognition of Peptide–MHC-I: Rule Makers and Breakers Christopher Szeto 1, Christian A. Lobos 1, Andrea T. Nguyen 1 and Stephanie Gras 1,2,* 1 Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; [email protected] (C.S.); [email protected] (C.A.L.); [email protected] (A.T.N.) 2 Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia * Correspondence: [email protected] Abstract: T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR–pMHC-I structures to date were determined within this time. Here, we review the new insights learned from these recent TCR–pMHC-I structures and their impact on T cell activation. Keywords: human leukocyte antigen (HLA); MHC class I; peptide antigens; TCR binding; αβ TCR; δβ TCR; γδ TCR 1. Overview of Structures and Status T cells use their surface receptor, called T cell receptor or TCR, to recognise peptides Citation: Szeto, C.; Lobos, C.A.; Nguyen, presented by major histocompatibility complex (MHC) molecules. The peptide presented A.T.; Gras, S. TCR Recognition of Peptide– by MHC can be derived from the host proteins (self-peptides), pathogens (virus and MHC-I: Rule Makers and Breakers. Int. bacteria), or tumours. The T cells need to differentiate between self and foreign peptides J. Mol. Sci. 2021, 22, 68. https://dx.doi. (including modify self), and are only activated upon MHC presentation of foreign epitopes. org/10.3390/ijms22010068 This recognition, driven by the TCR, is the critical first step of T cell activation preceding Received: 1 November 2020 the immune response. Accepted: 21 December 2020 MHC molecules, also called human leukocyte antigens or HLA in humans, are ex- Published: 23 December 2020 tremely polymorphic, ensuring that a wide range of peptides can be presented to T cells. MHC molecules are divided into two main classes, i.e., I and II, and are restricted to Publisher’s Note: MDPI stays neu- either CD8+ or CD4+ T cells, respectively. In this review, we focus on the TCR recognition tral with regard to jurisdictional claims of peptide (p) presented by MHC class I (MHC-I) molecules only. The MHC-I antigen in published maps and institutional binding cleft is closed at the N-terminal and C-terminal regions (Figure1A), while MHC-II affiliations. molecules have an open-ended cleft. These differences between open and closed ends of the cleft changes the preferred length of the bound peptide, whereby MHC-I often binds shorter (8–10 residues) peptides than MHC-II (>11 residues), albeit with some ex- ceptions [1]. MHC-I molecules have a series of pockets in the cleft, A to F, harbouring Copyright: © 2020 by the authors. Li- different chemical properties between different allomorphs resulting in the ability to bind censee MDPI, Basel, Switzerland. This different peptide repertoires. The B and F pockets are where the primary anchor residues, article is an open access article distributed the second and last positions of the peptide (P2 and PW, respectively), bind to the MHC-I under the terms and conditions of the Creative Commons Attribution (CC BY) (Figure1B). These residues are often conserved between different peptides binding to the license (https://creativecommons.org/ same MHC, for example, for peptides binding to HLA-B*35:01, a P2-Pro is often observed licenses/by/4.0/). as well as PW-Tyr [2,3]. Int. J. Mol. Sci. 2021, 22, 68. https://dx.doi.org/10.3390/ijms22010068 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 24 Int. J. Mol. Sci. 2021, 22, 68 2 of 26 MHC, for example, for peptides binding to HLA-B*35:01, a P2-Pro is often observed as well as PΩ-Tyr [2,3]. Figure 1. pMHC-IFigure 1. structure pMHC-I andstructure current and T cellcurrent receptor T cell (TCR)-pMHC-I receptor (TCR)-pMHC-I structures structures available. (available.A,B) Cleft (A of,B major) histocom- patibility complexCleft of major (MHC)-I histocompatibility molecule (pale complex pink) represented (MHC)-I molecule as surface (pale from pink) a top-down represented view as (A surface) and side view (B); the from a top-down view (A) and side view (B); the peptide is represented as pink spheres with the peptide is represented as pink spheres with the anchors residues at position 2 (P2) and at the last position (PW) in the B and anchors residues at position 2 (P2) and at the last position (PΩ) in the B and F pockets (B). (C,D) F pockets (B). (C,D) Number of TCR–pMHC-I structures solved per year (C) or per MHC-I (D). Number of TCR–pMHC-I structures solved per year (C) or per MHC-I (D). To recognise the highly polymorphic MHC and the large repertoire of peptides, TCRs To recognise the highly polymorphic MHC and the large repertoire of peptides, TCRs also need to be extremely diverse. Diversity in the TCR repertoire is achieved through the also need to be extremelyrandom genetic diverse. rearrangement Diversity in the of VariableTCR repertoire (V or TRV), is achieved Diversity through (D), and the Joining (J) gene random genetic segmentsrearrangement for TCR of Variableβ chain (V or and TRV), J for Diversity TCR α chain) (D), and [4]. Joining TCRs possess (J) gene three regions of segments for TCRvariability, β chain commonly(V and J for known TCR α as chain) the complementary [4]. TCRs possess determining three regions regions of (CDR1, CDR2, variability, commonlyand CDR3), known which as the make comple upmentary the antigen-binding determining siteregions that (CDR1, directly CDR2, interacts with pMHC. and CDR3), whichThe make CDR1 up and the CDR2 antigen-bindin regions areg germline-encodedsite that directly interacts by the V with gene pMHC. segment, whilst CDR3 The CDR1 and CDR2hyper-variability regions are germline-enco is further accentuatedded by the through V gene the segment, addition whilst or removal CDR3 of nucleotides hyper-variability(N) is atfurther V(D)J ac junctionscentuated [5]. through Theoretically, the addition the random or removal rearrangement of nucleotides of TCR gene segments (N) at V(D)J junctionscan give [5]. riseTheoretically, to a diversity the random of 1015–10 rearrangement20 T cell clonotypes of TCR [gene6]; however, segments thymic selection can give rise to eventsa diversity during of T10 cell15–10 maturation20 T cell clonotypes trims this [6]; down however, to a TCR thymic repertoire selection of 2.5 × 107 within events during T ancell individual maturation [7 ].trims This th providesis down enormousto a TCR repertoire T cell diversity of 2.5 to× 10 recognise7 within antigenican peptides individual [7]. Thispresented provides by MHCenormous molecules, T cell makingdiversity each to TCR–pMHCrecognise antigenic complex peptides structure unique in the presented by MHCrecognition molecules, of pathogensmaking each by TCR–pMHC the adaptive complex immune structure system. unique in the recognition of pathogensThe firstby the TCR–pMHC-I adaptive immune structure system. solved was by Garboczi and colleagues using X-ray The first TCR–pMHC-Icrystallography structure in 1996 solved for HLA-A*02:01 was by Garboczi presenting and colleagues the Tax using peptide X-ray from human T cell crystallography lymphotropicin 1996 for HLA-A*02:01 virus in complex presenting with the the A6 Tax TCR peptide (Table from1)[ 8 ].human Since then,T cell 81 unique TCR– lymphotropic viruspMHC-I in complex complexes with havethe A6 been TCR solved (Table and1) [8]. are Since available then, 81 in unique the Protein TCR– Data Bank (PDB; pMHC-I complexesTable have1), with been more solved than and half are of available these complexes in the Protein solved Data in the Bank last (PDB; 5 years (Figure1C). Table 1), with moreDespite than this half increase of these in complexes number over solved the last in fewthe last years, 5 years those (Figure 81 TCR–pMHC-I 1C). complexes Despite this increasestill representin number a over very the narrow last few slice years, of the those peptide 81 TCR–pMHC-I repertoire. For complexes example, thus far only still represent a 20very different narrow MHC slice of allomorphs the peptid havee repertoire. been crystallised For example, in complex thus far withonly 20 a TCR (Figure1D , different MHC allomorphsTable1). The have addition been crystall of theseised recent in complex structures with allowsa TCR (Figure us to observe 1D, Ta- how TCRs can ble 1). The additionrecognise of these HLA-A*01:01 recent structures [9]; HLA-A*11:01 allows us to observe [10]; HLA-B*07:02 how TCRs can [11 ];recognise HLA-B*37:01 [12]; HLA- HLA-A*01:01 [9];A*02:06 HLA-A*11:01 [13]; and, [10]; for theHLA-B* first07:02 time, HLA-C[11]; HLA-B*37:01 [14].