T Cell Antigen Recognition: Evolution-Driven Affinities

COMMENTARY Tcellantigenrecognition:Evolution-drivenaffinities COMMENTARY R´emy Bosseluta,1 T lymphocytes are essential for adaptive immune VJDC responses; most recognize peptides bound to cell- surface major histocompatibility complex (MHC) Germline molecules. The T cell receptor for antigen (TCR; on most T cells, a dimer of an α and a β chain associated with invariant signaling subunits) binds both peptide Rearranged and MHC determinants (1–3).Accordingly,forany given T cell, the TCR specificity is determined by both the antigenic peptide and the particular MHC TCR chain protein molecule the peptide binds. This property, called CDR 12 3 MHC restriction, is a critical feature of T cell antigen recognition. It has major functional and clinical im- pMHC MHC Peptide plications in settings such as organ transplantation binding contacts contacts and T cell-mediated therapies. MHC restriction re- sults from, and is often used to refer to, the ability of Fig. 1. Schematic showing the genomic regions generating domains of TCR chains before (Top) or after (Middle) TCR gene TCRαβ complexes to interact with MHC molecules. rearrangement, and the resulting protein products (Bottom). A new study by Krovi et al. in PNAS (4) clarifies the CDR1 and CDR2 are shown as purple boxes. CDR3 takes sequences controversial question of whether TCR gene se- from V, D, or J genomic regions (as color-coded) and untemplated quences have been skewed during evolution toward sequences (red boxes). TCRα genes have no D segments. MHC recognition. The dominant constraint governing TCR interactions with peptide-MHC complexes (pMHC) is the diversity of to interact with the specific allelic set of MHC molecules both components (2). In addition to being clonotypic carried by that individual. T cell precursors carrying such “ ” (one cell expressing a single TCR specificity), the mamma- useless TCRs undergo programmed cell death during lian TCR repertoire is highly diverse, with a potential for their development in the thymus (5). At the individual 15 “ ” − ∼10 specificities (1). Such diversity is generated in devel- level, this ensures that only useful self MHC-restricted oping T cells through rearrangement of genomic regions of TCRs contribute to the mature T cell repertoire, a process similar organization for both α and β loci (Fig. 1). Rearrange- called positive selection. But this leaves unanswered the ment generates de novo diversity within both α and β question of whether MHC restriction is “inscribed” in chains in a segment called complementarity determining germline TCR gene sequences, that is, whether the ge- region 3 (CDR3), through both deletion and nontemplated nomic sequences encoding TCR V regions generate a addition of nucleotides. Two additional segments, CDR1 preselection repertoire of TCRs skewed toward MHC and CDR2, carry diversity among variable (V) domains of recognition. TCR chains. All 3 CDRs form loops protruding from the core The structure and organization of TCRs is quite similar Vα or Vβ domain and mediate pMHC binding. Mirror- to that of immunoglobulins, which serve as receptors for ing TCR diversity, allelic diversification has made antigens in B lymphocytes and are secreted as antibodies MHC molecules highly polymorphic both at the spe- (2). Furthermore, immunoglobulin diversity is generated cies and individual level, a property essential to coun- in B cell precursors through a process highly similar to teract pathogen evasion of MHC presentation and that operating in T cell precursors at TCR gene loci. T cell defenses. However, unlike TCR, immunoglobulins recognize 3D The combined diversity of TCR and MHC molecules structures of diverse chemical composition, independently makes most TCRs generated by a given individual unable of their spatial context, and such binding does not require aLaboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Author contributions: R.B. wrote the paper. The author declares no competing interest. Published under the PNAS license. See companion article 10.1073/pnas.1909504116. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1916129116 PNAS Latest Articles | 1of3 Downloaded by guest on September 30, 2021 third-party molecules, whether MHC-related or not. Thus, if T and B all 3 CDRs) are generated from mouse T cell precursors lacking cell precursors carry similar receptors generated along similar pro- the constant (C) region of the TCRα gene (Fig. 1), which express cesses, why would the preselection TCR repertoire be MHC- no surface TCR despite normal TCRα gene rearrangement. Thus, restricted, whereas that of B cells is not? these libraries sample the preselection Vα repertoire. After ver- A conceptually appealing answer is that, despite their diver- ification of their diversity by deep sequencing, the libraries are sity, the germline-encoded CDR1 and CDR2 of TCRs, but not transfected into hybridoma cells that carry a reporter for TCR those of immunoglobulins, have been under evolutionary pres- engagement and express either a single TCRβ chain or a library sure to bind MHC molecules (3, 6). Although MHC and TCR di- of TCRβ chains obtained through the same approach. The ex- versity are not compatible with binary, sterically fixed interactions perimental design is tailored to express one TCR specificity per as for most ligand−receptor pairs (7), the idea of a TCR bias for cell, and transfected cells are evaluated for reactivity against MHC- MHC is supported by several lines of evidence. Analyses of TCR- expressing cell lines. Reactivity is assessed in both the absence and pMHC structures have shown that most use a similar (although presence of anti-MHC antibodies that prevent TCR-MHC interac- not identical) docking mode (2, 3): TCR α and β V domains are tions; the latter assay detects reactivity against non-MHC antigens obliquely positioned over the 2 MHC α-helices and peptide- expressed by the MHC-expressing cells or by the hybridoma itself, containing groove that make up the pMHC interaction interface. and therefore estimates MHC-independent binding. Most peptide contacts come from CDR3, whereas most MHC contacts are made by CDR1 and CDR2 residues. Although there The study by Krovi et al. builds a strong case that T is no general pattern of pairing between MHC allelic isoforms and cell MHC restriction is largely supported by a specific TCR V chains, comparison of multiple crystallographic structures suggests a loose correspondence between MHC built-in bias in TCR germline sequences. and conserved CDR1 and CDR2 residues that are needed for TCR- β pMHC interactions (8, 9). This supports the hypothesis that CDR1 TCR generated by pairing fixed TCR chain with members of α and CDR2 have evolved to be MHC-skewed, so that the TCR 5 diverse TCR libraries showed little or no MHC-independent repertoire is intrinsically MHC-biased at the species level, prior reactivity in these assays, whereas the frequency of MHC-reactive β to thymic selection. Indeed, earlier studies supported the idea of cells depended on which specific TCR was expressed. In this β an MHC-biased preselection TCR repertoire (10, 11). setting, the fixed TCR specificity conceivably restrained assay In apparent contrast with this idea, genetic analyses in mice sensitivity. Thus, Krovi et al. (4) generated hybridomas coex- β α α have identified αβ TCRs that recognize MHC-independent 3D pressing TCR and TCR libraries, therefore not limiting V pair- β αβ structures, including CD155, the mouse ortholog of the human ing to a few specific V . Remarkably, even though these TCR poliovirus receptor (12, 13). Cells expressing such MHC- pairs were randomly generated from preselection chains, 5 to independent TCRs are functionally similar to MHC-restricted 10% of them were MHC-reactive; in contrast, little or no MHC- T cells; as a population, they exhibit a broad TCR repertoire, independent reactivity was detected. While the sensitivity of the although with a trend to lower diversity than MHC-restricted cells. assay could be limiting for the detection of MHC-independent MHC-independent reactivity requires CDR3 and conserved reactivity, this should also affect the detection of MHC-dependent CDR2 residues previously reported to contribute to MHC reactiv- reactivity; thus, the data strongly support the idea of a germline ity (14–16). Thus, TCR gene rearrangement can generate MHC- skewing of TCR toward MHC reactivity. independent specificities, akin to those of immunoglobulins. This conclusion fits with earlier reports that coreceptors Importantly, while such TCRs are generated in the preselection rep- (notably CD4) are not required to generate an MHC-restricted ertoire, they are normally absent from the mature T cell repertoire repertoire (18). However, consistentwithanimportantroleof (consistent with the broader concept of MHC restriction) (13). In- coreceptors in establishing MHC restriction, Krovi et al. (4) find stead, the development of MHC-independent cells requires 2 that MHC-specific reactivity was enhanced by expression of an im- conditions: absence of MHC molecules from the thymus and proved CD4 (with higher affinity for its MHC target). Because disruption of genes encoding 2 surface “coreceptors,” CD4 and coreceptors only bind MHC and because positive selection is a CD8. CD4 and CD8 normally facilitate the selection of MHC- competitive process, the help provided by coreceptors would restricted T cell precursors through 2 mechanisms (17): 1) binding contribute to expunging the few MHC-independent TCRs gener- of invariant regions of MHC molecules, thereby promoting TCR ated by the rearrangement process. On the other side of the tethering to MHC, and 2) recruitment via their intracellular domain spectrum, precursors with high affinity for intrathymic ligands of a tyrosine kinase needed for TCR signal transduction. That are eliminated by TCR-induced death or redirected toward lineages the development of MHC-independent cells requires CD4 and with regulatory functions, and it would be interesting to see whether CD8 deletion raises the tantalizing possibility that coreceptors those are enriched for MHC-independent specificities (5).

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