title: Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin.
abstract: 4-1BB agonist antibody treatment induces a population of KLRG1(+) T cells that infiltrate melanoma tumors. We investigated the origin and function of these cells, as well as their place within established T cell paradigms. We find that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity. Distinct from described polarities, this T cell phenotype is driven by the T-box transcription factor Eomesodermin. Formation of this phenotype requires 4-1BB signaling on both T and antigen-presenting cells and the resulting production of the cytokines IL-27, IL-15, and IL-10. Furthermore, we find CD4(+) T cells bearing the signature features of this phenotype in the livers of mice infected with both bacterial and viral intracellular pathogens, suggesting a role for these cells in infectious immunity. These T cells constitute a novel phenotype that resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity.
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Curran
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Geiger
authors.forename: Welby
authors.initials: W
authors.lastname: Montalvo
authors.forename: Myoungjoo
authors.initials: M
authors.lastname: Kim
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; C491198:Eomes protein, mouse; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D020825:T-Box Domain Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
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