@article{1d466c0d5313479daf1541f8d1f5592c,
title = "Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function",
abstract = "Potent T cell responses against infections and malignancies require a rapid yet tightly regulated production of toxic effector molecules. Their production level is defined by post-transcriptional events at 3′ untranslated regions (3′ UTRs). RNA binding proteins (RBPs) are key regulators in this process. With an RNA aptamer-based capture assay, we identify >130 RBPs interacting with IFNG, TNF, and IL2 3′ UTRs in human T cells. RBP-RNA interactions show plasticity upon T cell activation. Furthermore, we uncover the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L, and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion does not rescue the dysfunctional phenotype, tumor-infiltrating T cells produce more cytokines and cytotoxic molecules, resulting in superior anti-tumoral T cell responses. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of T cell responses in health and disease.",
keywords = "ATXN2L, CP: Immunology, HuR, RNA binding proteins, ZC3HAV1, ZFP36L1, cytokines, human T cells, post-transcriptional regulation, tumor-infiltrating T cells",
author = "Branka Popovi{\'c} and Nicolet, {Beno{\^i}t P.} and Aur{\'e}lie Guislain and Sander Engels and Jurgens, {Anouk P.} and Natali Paravinja and {Freen-van Heeren}, {Julian J.} and {van Alphen}, {Floris P. J.} and {van den Biggelaar}, Maartje and Fiamma Salerno and Wolkers, {Monika C.}",
note = "Funding Information: We thank the animal caretakers of the NKI and the Sanquin FACS facility; G. Stoecklin (University of Heidelberg) for the 4xS1m aptamer construct; T. Schumacher (Netherlands Cancer Institute) for providing MART-1 TCR viral supernatants and Mel526 and Mel888 tumor cell lines; M. Hoogenboezem, N. Zandhuis, S. Castenmiller, N. {\v S}o{\v s}tari{\'c}, and I. Foskolou for technical help; and D. Amsen, M. Nolte, and B. van Steensel for critical reading of the manuscript. This research was supported by the Dutch Cancer Society (KWF Kankerbestrijding, 10132), European Research Council consolidator award PRINTERS 817533, and Oncode Institute, all to M.C.W.; the Landsteiner Foundation for Blood Transfusion Research grant 2103 to B.P. and M.C.W.; and the Amsterdam Institute for Infection and Immunity extension grant for postdocs (25262) to B.P. B.P. F.S. and M.C.W. designed experiments. B.P. A.G. S.E. A.P.J. N.P. J.J.F.-v.H. F.P.J.v.A. and F.S. performed experiments. B.P. B.P.N. A.P.J. M.v.d.B. F.P.J.v.A. and M.C.W. analyzed the data. B.P. and M.C.W. wrote the manuscript. All authors have read and approved the submitted version. M.C.W. supervised the project. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: We thank the animal caretakers of the NKI and the Sanquin FACS facility; G. Stoecklin (University of Heidelberg) for the 4xS1m aptamer construct; T. Schumacher (Netherlands Cancer Institute) for providing MART-1 TCR viral supernatants and Mel526 and Mel888 tumor cell lines; M. Hoogenboezem, N. Zandhuis, S. Castenmiller, N. {\v S}o{\v s}tari{\'c}, and I. Foskolou for technical help; and D. Amsen, M. Nolte, and B. van Steensel for critical reading of the manuscript. This research was supported by the Dutch Cancer Society ( KWF Kankerbestrijding , 10132 ), European Research Council consolidator award PRINTERS 817533 , and Oncode Institute , all to M.C.W.; the Landsteiner Foundation for Blood Transfusion Research grant 2103 to B.P. and M.C.W.; and the Amsterdam Institute for Infection and Immunity extension grant for postdocs ( 25262 ) to B.P. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = may,
day = "30",
doi = "https://doi.org/10.1016/j.celrep.2023.112419",
language = "English",
volume = "42",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}