title: CD134 plus CD137 dual costimulation induces Eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation.
abstract: Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can effectively target tumors, but until now the pathways that govern their differentiation have been poorly understood. We demonstrate that CD134 (OX40) costimulation programs naive self- and virus-reactive CD4 T cells to undergo in vivo differentiation into cytotoxic Th1 effectors. CD137 (4-1BB) costimulation maximized clonal expansion, and IL-2 was necessary for cytotoxic Th1 differentiation. Importantly, the T-box transcription factor Eomesodermin was critical for inducing the cytotoxic marker granzyme B. CD134 plus CD137 dual costimulation also imprinted a cytotoxic phenotype on bystanding CD4 T cells. Thus, to our knowledge, the current study identifies for the first time a specific costimulatory pathway and an intracellular mechanism relying on Eomesodermin that induces both Ag-specific and bystander cytotoxic CD4 Th1 cells. This mechanism might be therapeutically useful because CD134 plus CD137 dual costimulation induced CD4 T cell-dependent tumoricidal function in a mouse melanoma model.
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors: Harry Z
authors: HZ
authors: Qui
authors: Adam T
authors: AT
authors: Hagymasi
authors: Suman
authors: S
authors: Bandyopadhyay
authors: Marie-Clare
authors: MC
authors: St Rose
authors: Raghunath
authors: R
authors: Ramanarasimhaiah
authors: Antoine
authors: A
authors: Ménoret
authors: Robert S
authors: RS
authors: Mittler
authors: Scott M
authors: SM
authors: Gordon
authors: Steven L
authors: SL
authors: Reiner
authors: Anthony T
authors: AT
authors: Vella
authors: Adam J
authors: AJ
authors: Adler
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism
chemical_list: C491198:Eomes protein, mouse; D053262:Receptors, OX40; D020825:T-Box Domain Proteins; C505717:Tnfrsf4 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9