| First Author | Giordano M | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 30 | Pages | 11115-20 |
| PubMed ID | 25024217 | Mgi Jnum | J:212245 |
| Mgi Id | MGI:5578389 | Doi | 10.1073/pnas.1406259111 |
| Citation | Giordano M, et al. (2014) The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. Proc Natl Acad Sci U S A 111(30):11115-20 |
| abstractText | The transcription factor NF-kappaB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-kappaB 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 IFNgamma, correlated with sustained nuclear expression of NF-kappaB 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-kappaB 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 IFNgamma and TNFalpha 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. |
