title: Active STAT5 regulates T-bet and eomesodermin expression in CD8 T cells and imprints a T-bet-dependent Tc1 program with repressed IL-6/TGF-β1 signaling.
abstract: In adoptive therapy, CD8 T cells expressing active STAT5 (STAT5CA) transcription factors were found to be superior to unmanipulated counterparts in long-term persistence, capacity to infiltrate autochthonous mouse melanomas, thrive in their microenvironment, and induce their regression. However, the molecular mechanisms sustaining these properties were undefined. In this study, we report that STAT5CA induced sustained expression of genes controlling tissue homing, cytolytic granule composition, type 1 CD8 cytotoxic T cell-associated effector molecules granzyme B(+), IFN-γ(+), TNF-α(+), and CCL3(+), but not IL-2, and transcription factors T-bet and eomesodermin (Eomes). Chromatin immunoprecipitation sequencing analyses identified the genes possessing regulatory regions to which STAT5 bound in long-term in vivo maintained STAT5CA-expressing CD8 T cells. This analysis identified 34% of the genes differentially expressed between STAT5CA-expressing and nonexpressing effector T cells as direct STAT5CA target genes, including those encoding T-bet, Eomes, and granzyme B. Additionally, genes encoding the IL-6R and TGFbRII subunits were stably repressed, resulting in dampened IL-17-producing CD8 T cell polarization in response to IL-6 and TGF-β1. The absence of T-bet did not affect STAT5CA-driven accumulation of the T cells in tissue or their granzyme B expression but restored IL-2 secretion and IL-6R and TGFbRII expression and signaling, as illustrated by IL-17 induction. Therefore, concerted STAT5/T-bet/Eomes regulation controls homing, long-term maintenance, recall responses, and resistance to polarization towards IL-17-producing CD8 T cells while maintaining expression of an efficient type 1 CD8 cytotoxic T cell program (granzyme B(+), IFN-γ(+)).
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, Marseille 13288, France;
authors.forename: Magali
authors.initials: M
authors.lastname: Grange
authors.forename: Grégory
authors.initials: G
authors.lastname: Verdeil
authors.forename: Fanny
authors.initials: F
authors.lastname: Arnoux
authors.forename: Aurélien
authors.initials: A
authors.lastname: Griffon
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.forename: Julien
authors.initials: J
authors.lastname: Maurizio
authors.forename: Michel
authors.initials: M
authors.lastname: Buferne
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: C491198:Eomes protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D053773:Transforming Growth Factor beta1