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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmunity / physiology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cytokines / genetics
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Cytokines / immunology
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Cytokines / metabolism
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Lectins, C-Type
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Melanoma / genetics
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Melanoma / immunology
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Knockout
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Receptors, Immunologic / metabolism
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T-Box Domain Proteins / biosynthesis
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology*
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / agonists
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
Substances
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Cytokines
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Eomes protein, mouse
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Klrg1 protein, mouse
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Lectins, C-Type
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Receptors, Immunologic
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T-Box Domain Proteins
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Tumor Necrosis Factor Receptor Superfamily, Member 9