Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function
Branka Popović,
Benoît P. Nicolet,
Aurélie Guislain,
Sander Engels,
Anouk P. Jurgens,
Natali Paravinja,
Julian J. Freen-van Heeren,
Floris P.J. van Alphen,
Maartje van den Biggelaar,
Fiamma Salerno,
Monika C. Wolkers
Affiliations
Branka Popović
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Benoît P. Nicolet
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Aurélie Guislain
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Sander Engels
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Anouk P. Jurgens
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Natali Paravinja
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Julian J. Freen-van Heeren
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Floris P.J. van Alphen
Department of Molecular Hematology, Sanquin Research, 1066 CX Amsterdam, the Netherlands
Maartje van den Biggelaar
Department of Molecular Hematology, Sanquin Research, 1066 CX Amsterdam, the Netherlands
Fiamma Salerno
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Monika C. Wolkers
Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam Immunity and Infection and Cancer Center Amsterdam, the Amsterdam University Medical Center, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands; Corresponding author
Summary: 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.
