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This review discusses how recent methodological developments\u2014including high\u2010dimensional TCR discovery strategies, physiological receptor engineering, and longitudinal in\u00a0vivo analyses\u2014have reshaped our understanding of TCR\u2010driven immune responses. Recruitment into immune responses originates from diverse na\u00efve precursor pools and results in polyclonal populations in which multiple clonotypes contribute to antigen recognition. Within such populations, receptor properties, such as TCR avidity, influence the likelihood of recruitment, expansion, and persistence. However, the impact of these parameters depends strongly on biological context, including antigen availability, cellular competition, and tissue environment. Physiological engineering approaches, such as orthotopic TCR replacement, now enable causal interrogation of receptor function while preserving endogenous regulatory control. Together with advances in spatial and longitudinal profiling of human immune responses, these approaches allow increasingly precise analyses of connections between TCR identity and T cell fate. Integrating insights across antigen discovery, receptor engineering, and in\u00a0vivo dynamics suggests that TCR biology is shaped by the interplay of receptor sequence, regulatory context, and tissue environment across time. Understanding these relationships will be essential for interpreting immune responses and for guiding the rational design of T cell\u2010based immunotherapies.<\/jats:p>","DOI":"10.1111\/imr.70136","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:17:09Z","timestamp":1780633029000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The T Cell Receptor: Molecular Sensor, Therapeutic Mediator and Probabilistic Driver of Adaptive Immunity"],"prefix":"10.1111","volume":"340","author":[{"given":"Kilian","family":"Schober","sequence":"first","affiliation":[{"name":"Mikrobiologisches Institut\u2013Klinische Mikrobiologie, Immunologie und Hygiene Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU Profile Center Immunomedicine FAU Erlangen\u2010N\u00fcrnberg  Erlangen 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