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T-bet is the lineage-specifying transcription factor for CD4 + T H 1 cells. T-bet has also been found in other CD4 + T cell subsets, including T H 17 cells and Treg, where it modulates their functional characteristics. However, we lack information on when and where T-bet is expressed during T cell differentiation and how this impacts T cell differentiation and function. To address this, we traced the ontogeny of T-bet-expressing cells using a fluorescent fate-mapping mouse line. We demonstrate that T-bet is expressed in a subset of CD4 + T cells that have naïve cell surface markers and transcriptional profile and that this novel cell population is phenotypically and functionally distinct from previously described populations of naïve and memory CD4 + T cells. Naïve-like T-bet-experienced cells are polarized to the T H 1 lineage, predisposed to produce IFN-γ upon cell activation, and resist repolarization to other lineages in vitro and in vivo. These results demonstrate that lineage-specifying factors can polarize T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T-helper response., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC., Competing Interests: Competing interest statement S.A.Q., K.S.P. and C.S. are co-founders of Achilles Therapeutics. C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana and Boehringer-Ingelheim. C.S. has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. R.R., N.M. and G.A.W. have stock options in and have consulted for Achilles Therapeutics. J.L.R and M.A.B have consulted for Achilles Therapeutics. P.D.B and M.W.S are employees of Achilles Therapeutics.