The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET− expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS
Disclosures: S. Fuchs reported being an employee of F. Hoffmann-La Roche (Roche) AG. F.G. Kapp reported personal fees from Novartis outside the submitted work. M.G. Seidel reported personal fees from Jazz Pharmaceuticals, personal fees from Shire, personal fees from Novartis, and personal fees from Amgen outside the submitted work. T. Kalina reported being a Scientific Board member of Scailyte AG. B. Grimbacher reported personal fees from University Hospital Freiburg, personal fees from Pharmaceutical companies, personal fees from Diagnostic companies, grants from Pharmaceutical companies, and grants from Public funding agencies outside the submitted work. A.P. Frei reported being an employee of F. Hoffmann-La Roche (Roche) AG. S. Ehl reported grants from UCB outside the submitted work. No other disclosures were reported.
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Maria Elena Maccari, Sebastian Fuchs, Patrick Kury, Geoffroy Andrieux, Simon Völkl, Bertram Bengsch, Myriam Ricarda Lorenz, Maximilian Heeg, Jan Rohr, Sabine Jägle, Carla N. Castro, Miriam Groß, Ursula Warthorst, Christoph König, Ilka Fuchs, Carsten Speckmann, Julian Thalhammer, Friedrich G. Kapp, Markus G. Seidel, Gregor Dückers, Stefan Schönberger, Catharina Schütz, Marita Führer, Robin Kobbe, Dirk Holzinger, Christian Klemann, Petr Smisek, Stephen Owens, Gerd Horneff, Reinhard Kolb, Nora Naumann-Bartsch, Maurizio Miano, Julian Staniek, Marta Rizzi, Tomas Kalina, Pascal Schneider, Anika Erxleben, Rolf Backofen, Arif Ekici, Charlotte M. Niemeyer, Klaus Warnatz, Bodo Grimbacher, Hermann Eibel, Andreas Mackensen, Andreas Philipp Frei, Klaus Schwarz, Melanie Boerries, Stephan Ehl, Anne Rensing-Ehl; A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS. J Exp Med 1 February 2021; 218 (2): e20192191. doi: https://doi.org/10.1084/jem.20192191
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