Clancy-Thompson Eleanor, Chen Gui Zhen, Tyler Paul M, Servos Mariah M, Barisa Marta, Brennan Patrick J, Ploegh Hidde L, Dougan Stephanie K
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215.
Whitehead Institute for Biomedical Research, Cambridge, MA 02242; and.
J Immunol. 2017 Jul 1;199(1):159-171. doi: 10.4049/jimmunol.1700214. Epub 2017 Jun 2.
Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-γ, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vβ7 or Vβ8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORγt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity.
不变自然杀伤T细胞（iNKT）功能亚群由关键转录因子和细胞因子的输出所定义，如白细胞介素-4（IL-4）、干扰素-γ（IFN-γ）、白细胞介素-17（IL-17）和白细胞介素-10（IL-10）。为了研究T细胞受体（TCR）特异性如何决定iNKT功能，我们利用体细胞核移植技术从iNKT细胞核中克隆出了三系小鼠。每一系都使用恒定的Vα14Jα18 TCRα与独特的Vβ7或Vβ8.2亚基配对。我们检测了组织归巢、早幼粒细胞白血病锌指蛋白（PLZF）、T盒转录因子（T-bet）和维甲酸相关孤儿受体γt（RORγt）的表达以及细胞因子谱，发现尽管单克隆iNKT细胞可分化为所有功能亚群，但NKT17谱系会根据所表达的TCR而减少或增加。我们在有限稀释骨髓嵌合体中检测了iNKT在胸腺中的发育情况，结果表明较高的TCR亲和力与较高的PLZF表达以及降低的T-bet表达相关。iNKT功能亚群表现出不同的组织分布模式。尽管每个单克隆TCR都显示出一种固有的亚群分布偏好，这在所有检测的组织中都很明显，但iNKT细胞因子谱更多地因起源组织而异而非因TCR特异性而异。
