Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, T-cell activation, tumor immunity, inflammation, NF-KAPPA-B, C-REL, GENE-EXPRESSION, MELANOMA, TOLERANCE, IMMUNITY, ANTIGEN, MICE, INFLAMMATION, DEFICIENCY, Animals, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Cysteine Endopeptidases, Humans, Immunity, Cellular, Interferon-gamma, Interleukin-2, Intracellular Signaling Peptides and Proteins, Melanoma, Mice, Mice, Knockout, NF-kappa B, Tumor Necrosis Factor alpha-Induced Protein 3, Tumor Necrosis Factor-alpha

Abstract:

The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.