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To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A ∗ 02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer., Competing Interests: Declaration of interests C.L.M. is a founder of, holds equity in, and receives consulting fees from Lyell Immunopharma and receives consulting fees from NeoImmuneTech, Nektar, Apricity, and Roche. J.W.N. reports research support from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Takeda Pharmaceuticals, Nektar Therapeutics, Adaptimmune, and GSK and has served in a consulting or advisory role for AstraZeneca, Genentech/Roche, Exelixis Inc., Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, Calithera Biosciences, Amgen, Regeneron Pharmaceuticals, Natera, and Iovance Biotherapeutics. H.A.W. has received research support from Celgene, Clovis Oncology, Genentech/Roche, Arrys Therapeutics, Novartis, Merck, BMS, Exelixis, Lilly, Pfizer, and has participated on the advisory boards of Helsinn, Mirati, Cellworks, Genentech/Roche, Merck, and ITMIG. N.S.L. has received research funding from Intuitive Foundation and Auspex Diagnostics. E.S. is a consultant for Lyell Immunopharma. L.L. is a consultant for Lyell Immunopharma. S.A.F. is consulting for Lonza PerMed and Samsara BioCapital. M.D. reports research funding from Varian Medical Systems and Illumina; ownership interest in CiberMed and Foresight Diagnostics; patent filings related to cancer biomarkers; paid consultancy from Roche, AstraZeneca, BioNTech, Genentech, Novartis, and Gritstone Oncology; and travel/honoraria from Reflexion. K.C.G. is founder of 3T therapeutics. I.I.W. has received honoraria from Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD. I.I.W. is also supported by Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. J.Z. reports grants from Merck and Johnson & Johnson, as well as adversary/consulting/Hornoraria fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, OrigMed, and Roche outside the submitted work. This study was supported in part by a Cancer Prevention Research Institute of Texas Multi-Investigator Research Award (grant number RP160668) and the University of Texas Lung Specialized Programs of Research Excellence grant (grant number P50CA70907). S.-H.C., D.T., C.L.M., and M.M.D have a patent related to this work., (Copyright © 2021. Published by Elsevier Inc.)

Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8 + T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche., Competing Interests: Declaration of Interests D.W.G. is a consultant and equity holder of Indalo Therapeutics, which provided compound CWHM-12. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CD4 + T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4 + T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4 + memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4 + T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4 + T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection., Competing Interests: Declaration of Interests P.B. and A.S. are consultants of Miltenyi Biotec, who own IP rights concerning parts of the ARTE technology. M.J.G.T.V. has received research grants from 3M, Astellas Pharma, Biontech, DaVolterra, Evonik, Gilead Sciences, Glycom, Immunic, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics, and Takeda Pharmaceutical; speakers fees from Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, and Pfizer; and consultation fees from Alb Fils Kliniken GmbH, Arderypharm, Astellas Pharma, DaVolterra, Farmak International Holding GmbH, Ferring, Immunic AG, MaaT Pharma, Merck/MSD, and SocraTec R&D GmbH. F.L. discloses speaker honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, and Fresenius; travel funding from Merck, Grifols, and Bayer; and serves on advisory boards for Roche, Biogen, and Alexion. P.K. has received non-financial scientific grants from Miltenyi Biotec GmbH and the CECAD, University of Cologne, outside the submitted work. O.A.C. has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The process of affinity maturation, whereby T and B cells bearing antigen receptors with optimal affinity to the relevant antigen undergo preferential expansion, is a key feature of adaptive immunity. Natural killer (NK) cells are innate lymphocytes capable of "adaptive" responses after cytomegalovirus (CMV) infection. However, whether NK cells are similarly selected on the basis of their avidity for cognate ligand is unknown. Here, we showed that NK cells with the highest avidity for the mouse CMV glycoprotein m157 were preferentially selected to expand and comprise the memory NK cell pool, whereas low-avidity NK cells possessed greater capacity for interferon-γ (IFN-γ) production. Moreover, we provide evidence for avidity selection occurring in human NK cells during human CMV infection. These results delineate how heterogeneity in NK cell avidity diversifies NK cell effector function during antiviral immunity, and how avidity selection might serve to produce the most potent memory NK cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3(+) regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3(+) Treg cells in Aire(+/+) mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%-90%, averaging over 50%) of CD4(+) T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments., (Copyright © 2013 Elsevier Inc. All rights reserved.)

After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen-specific T cells even though they are not reactive to the same agonist as their targets. Instead, an isolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptide-MHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimmune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multiple responses, preserving the valuable diversity of the repertoire., (Copyright © 2012 Elsevier Inc. All rights reserved.)

αβ T cell receptors (TCRs) bind specifically to foreign antigens presented by major histocompatibility complex proteins (MHC) or MHC-like molecules. Accumulating evidence indicates that the germline-encoded TCR segments have features that promote binding to MHC and MHC-like molecules, suggesting coevolution between TCR and MHC molecules. Here, we assess directly the evolutionary conservation of αβ TCR specificity for MHC. Sequence comparisons showed that some Vβs from distantly related jawed vertebrates share amino acids in their complementarity determining region 2 (CDR2). Chimeric TCRs containing amphibian, bony fish, or cartilaginous fish Vβs can recognize antigens presented by mouse MHC class II and CD1d (an MHC-like protein), and this recognition is dependent upon the shared CDR2 amino acids. These results indicate that features of the TCR that control specificity for MHC and MHC-like molecules were selected early in evolution and maintained between species that last shared a common ancestor more than 400 million years ago., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The T cell receptor (TCR) and CD8 bind peptide-major histocompatibility complex (pMHC) glycoproteins to initiate adaptive immune responses, yet the trimolecular binding kinetics at the T cell membrane is unknown. By using a micropipette adhesion frequency assay, we show that this kinetics has two stages. The first consists of TCR-dominant binding to agonist pMHC. This triggers a second stage consisting of a step increase in adhesion after a one second delay. The second-stage binding requires Src family kinase activity to initiate CD8 binding to the same pMHC engaged by the TCR. This induced trimeric-cooperative interaction enhances adhesion synergistically to favor potent ligands, which further amplifies discrimination. Our data reveal a TCR-CD8 positive-feedback loop involved in initial signaling steps that is sensitive to a single pMHC is rapid, reversible, synergistic, and peptide discriminative., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Efficient immune attack of malignant disease requires the concerted action of both CD8+ CTL and CD4+ Th cells. We used human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic mice, in which the mouse CD8 molecule cannot efficiently interact with the alpha3 domain of A2.1, to generate a high-affinity, CD8-independent T cell receptor (TCR) specific for a commonly expressed, tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the human p53 tumor suppressor protein. Retroviral expression of this CD8-independent, p53-specific TCR into human T cells imparted the CD8+ T lymphocytes with broad tumor-specific CTL activity and turned CD4+ T cells into potent tumor-reactive, p53A2.1-specific Th cells. Both T cell subsets were cooperative and interacted synergistically with dendritic cell intermediates and tumor targets. The intentional redirection of both CD4+ Th cells and CD8+ CTL by the same high-affinity, CD8-independent, tumor-specific TCR could provide the basis for novel broad-spectrum cancer immunotherapeutics.

Activating and inhibitory CD94/NKG2 receptors regulate CTL responses by altering TCR signaling, thus modifying antigen activation thresholds set during thymic selection. To determine whether their expression was linked to TCR specificity, we examined the TCR repertoire of oligoclonal CTL expansions found in human blood and tissues. High-resolution TCR repertoire analysis revealed that commitment to inhibitory NKG2A expression was a clonal attribute developmentally acquired after TCR expression and during antigen encounter, whereas actual surface expression depended on recent TCR engagement. Further, CTL clones expressing sequence-related TCR, and therefore sharing the same antigen specificity, invariably shared the same NKG2A commitment. These findings suggest that TCR antigenic specificity dictates NKG2A commitment, which critically regulates subsequent activation of CTL.