TCF1 and its homologue LEF1 are historically known as effector transcription factors downstream of the WNT signalling pathway and are essential for early T cell development. Recent advances bring TCF1 into the spotlight for its versatile, context-dependent functions in regulating mature T cell responses. In the cytotoxic T cell lineages, TCF1 is required for the self-renewal of stem-like CD8+ T cells generated in response to viral or tumour antigens, and for preserving heightened responses to checkpoint blockade immunotherapy. In the helper T cell lineages, TCF1 is indispensable for the differentiation of T follicular helper and T follicular regulatory cells, and crucially regulates immunosuppressive functions of regulatory T cells. Mechanistic investigations have also identified TCF1 as the first transcription factor that directly modifies histone acetylation, with the capacity to bridge transcriptional and epigenetic regulation. TCF1 also has the potential to become an important clinical biomarker for assessing the prognosis of tumour immunotherapy and the success of viral control in treating HIV and hepatitis C virus infection. Here, we summarize the key findings on TCF1 across the fields of T cell immunity and reflect on the possibility of exploring TCF1 and its downstream transcriptional programmes as therapeutic targets for improving antiviral and antitumour immunity.
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