Zhao et al. engineered a chimera of an IL-2 receptor domain linked to the transmembrane and intracellular domains of diverse, orthogonal (o) cytokine receptors to explore novel JAK/STAT outputs in T cells. Many o-receptors enhanced tumor control, despite divergent pSTAT/gene expression patterns. oIL-22R promoted a Tscm phenotype in vivo, which correlated with chromatin alterations, including enrichment of BACH2 (stemness)- and AP1 (cytotoxicity)-bound motifs. oIL4R induced Th2/Tc2 differentiation, with maintenance of Th1 cytokines. oGCSFR promoted myeloid gene expression and endowed phagocytic capacity, without compromising T cell identity.
Contributed by Morgan Janes
ABSTRACT: T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform2-4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK-STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Molecular and Cellular Physiology, Stanford Univer
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. (4) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (13) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. akalbasi@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. akalbasi@stanford.edu. (14) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
