Journal
IMMUNITY
Volume 49, Issue 6, Pages 1049-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.10.008
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Funding
- NIH [AI029564, CA156330, DK094779, CA10068, U19AI109965]
- Japanese vaccine research fellowship (Japan Foundation for Pediatric Research)
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Appropriate immune responses require a fine balance between immune activation and attenuation. NLRC3, a non-inflammasome-forming member of the NLR innate immune receptor family, attenuates inflammation in myeloid cells and proliferation in epithelial cells. T lymphocytes express the highest amounts of Nlrc3 transcript where its physiologic relevance is unknown. We show that NLRC3 attenuated interferon-gamma and TNF expression by CD4(+) T cells and reduced T helper 1 (Th1) and Th17 cell proliferation. Nlrc3(-/-) mice exhibited increased and prolonged CD4(+) T cell responses to lymphocytic choriomeningitis virus infection andworsened experimental autoimmune encephalomyelitis (EAE). These functions of NLRC3 were executed in a T-cell-intrinsic fashion: NLRC3 reduced K63-linked ubiquitination of TNF-receptor-associated factor 6 (TRAF6) to limit NF-kappa B activation, lowered phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and diminished glycolysis and oxidative phosphorylation. This study reveals an unappreciated role for NLRC3 in attenuating CD4(+) T cell signaling and metabolism.
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