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-γ 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 and worsened 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-κB 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.

适当的免疫反应需要在免疫激活和减毒之间达到良好的平衡。NLRC3是NLR先天性免疫受体家族的非炎症小体形成成员，可减轻髓样细胞的炎症和上皮细胞的增殖。T淋巴细胞表达最高的Nlrc3转录物，而其生理学相关性未知。我们显示NLRC3减毒了CD4 ⁺ T细胞的干扰素-γ和TNF表达，并减少了T辅助1（Th1）和Th17细胞的增殖。Nlrc3 ^-/-小鼠表现出增加的CD4 ⁺和延长的CD ⁺T细胞对淋巴细胞性脉络膜脑膜炎病毒感染和实验性自身免疫性脑脊髓炎（EAE）恶化的反应。NLRC3的这些功能以T细胞固有的方式执行：NLRC3减少了K63连锁的TNF受体相关因子6（TRAF6）的泛素化，以限制NF-κB活化，降低了真核翻译起始因子4E结合蛋白的磷酸化。 1（4E-BP1），并减少了糖酵解和氧化磷酸化作用。这项研究揭示了NLRC3在减弱CD4 ⁺ T细胞信号传导和代谢中的重要作用。