CD4 and CD8 co-receptors define distinct lineages of T cells restricted by major histocompatibility complex (MHC) Class II and I molecules, respectively. Co-receptors interact with the T cell receptor (TCR) at the surface of MHC-restricted T cells to facilitate antigen recognition, thymic selection, and functional differentiation. T cells also recognize lipid antigens presented by CD1 molecules, but the role that CD4 and CD8 play in lipid antigen recognition is unknown. We studied the effect of CD4 and CD8 on the avidity, activation, and function of T cells specific for two CD1b-presented mycobacterial lipid antigens, glucose monomycolate (GMM) and diacylated sulfoglycolipids (SGL). In a human cohort study using SGL-loaded CD1b tetramers, we discovered a hierarchy among SGL-specific T cells in which T cells expressing the CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity (MFI) than CD4-CD8- T cells. To determine the role of the TCR co-receptor in lipid antigen recognition, we exogenously expressed GMM and SGL-specific TCRs in Jurkat or polyclonal T cells and quantified tetramer staining and activation thresholds. Transduced CD4+ primary T cells bound the lipid-loaded CD1b tetramer with a higher MFI than CD8+ primary T cells, and transduced CD8+ Jurkat cells bound the SGL-CD1b tetramer with higher MFI than CD4-CD8- Jurkat cells. The presence of either co-receptor also decreased the threshold for IFN-γ secretion. Further, co-receptor expression increased surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Finally, we used single-cell sequencing to define the TCR repertoire and ex vivo functional profiles of SGL-specific T cells from individuals with M.tb disease. We found that CD8+ T cells specific for SGL express canonical markers associated with cytotoxic T lymphocytes, while CD4+ T cells could be classified as T regulatory or T follicular helper cells. Among SGL-specific T cells, only those expressing the CD4 co-receptor also expressed Ki67, suggesting that they were actively proliferating at the time of sample collection. Together, these data reveal that expression of CD4 and CD8 co-receptor modulates TCR avidity for lipid antigen, leading to functional diversity and differences in in vivo proliferation during M.tb disease.

中文翻译：

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CD4和CD8共同受体调节CD1b限制T细胞的功能亲和力。

CD4和CD8共同受体分别定义了受主要组织相容性复合体（MHC）II类和I类分子限制的T细胞谱系。辅助受体在受MHC限制的T细胞表面与T细胞受体（TCR）相互作用，以促进抗原识别，胸腺选择和功能分化。T细胞还可以识别CD1分子呈递的脂质抗原，但CD4和CD8在脂质抗原识别中所起的作用尚不清楚。我们研究了CD4和CD8对T细胞的亲和力，激活和功能的影响，该T细胞对两种CD1b呈递的分枝杆菌脂质抗原，葡萄糖一霉菌酸酯（GMM）和二酰化磺基糖脂（SGL）具有特异性。在一项使用SGL加载的CD1b四聚体的人类队列研究中，我们发现了SGL特异性T细胞之间的等级关系，其中表达CD4或CD8共受体染色的T细胞比CD4-CD8- T细胞具有更高的四聚体平均荧光强度（MFI）。为了确定TCR共受体在脂质抗原识别中的作用，我们在Jurkat或多克隆T细胞中外源表达了GMM和SGL特异性TCR，并定量了四聚体染色和激活阈值。转导的CD4 +初级T细胞以比CD8 +初级T细胞更高的MFI结合脂质装载的CD1b四聚体，而转导的CD8 + Jurkat细胞以比CD4-CD8- Jurkat细胞更高的MFI结合SGL-CD1b四聚体。任一种共受体的存在也降低了IFN-γ分泌的阈值。此外，共受体表达增加了CD3ε的表面表达，表明增加了四聚体结合和激活的机制。最后，我们使用单细胞测序定义了患有M.tb疾病的个体的SGL特异性T细胞的TCR库和离体功能概况。我们发现特异性针对SGL的CD8 + T细胞表达与细胞毒性T淋巴细胞相关的典型标志物，而CD4 + T细胞则可归类为T调节性或T滤泡性辅助细胞。在SGL特异性T细胞中，只有表达CD4共受体的细胞也表达Ki67，这表明它们在样品收集时正在活跃地增殖。总之，这些数据揭示了CD4和CD8共受体的表达调节了TCR对脂质抗原的亲和力，导致功能多样性和M.tb疾病期间体内增殖的差异。我们使用单细胞测序来定义患有M.tb疾病的个体的SGL特异性T细胞的TCR库和离体功能概况。我们发现特异性针对SGL的CD8 + T细胞表达与细胞毒性T淋巴细胞相关的典型标志物，而CD4 + T细胞则可归类为T调节性或T滤泡性辅助细胞。在SGL特异性T细胞中，只有表达CD4共受体的细胞也表达Ki67，这表明它们在样品收集时正在活跃地增殖。总之，这些数据揭示了CD4和CD8共受体的表达调节了TCR对脂质抗原的亲和力，导致功能多样性和M.tb疾病期间体内增殖的差异。我们使用单细胞测序来定义患有M.tb疾病的个体的SGL特异性T细胞的TCR库和离体功能概况。我们发现特异性针对SGL的CD8 + T细胞表达与细胞毒性T淋巴细胞相关的典型标志物，而CD4 + T细胞则可归类为T调节性或T滤泡性辅助细胞。在SGL特异性T细胞中，只有表达CD4共受体的细胞也表达Ki67，这表明它们在样品收集时正在活跃地增殖。总之，这些数据揭示了CD4和CD8共受体的表达调节了TCR对脂质抗原的亲和力，导致功能多样性和M.tb疾病期间体内增殖的差异。我们发现特异性针对SGL的CD8 + T细胞表达与细胞毒性T淋巴细胞相关的典型标志物，而CD4 + T细胞则可归类为T调节性或T滤泡性辅助细胞。在SGL特异性T细胞中，只有表达CD4共受体的细胞也表达Ki67，这表明它们在样品收集时正在活跃地增殖。总之，这些数据揭示了CD4和CD8共受体的表达调节了TCR对脂质抗原的亲和力，导致功能多样性和M.tb疾病期间体内增殖的差异。我们发现特异性针对SGL的CD8 + T细胞表达与细胞毒性T淋巴细胞相关的典型标志物，而CD4 + T细胞则可归类为T调节性或T滤泡性辅助细胞。在SGL特异性T细胞中，只有表达CD4共受体的细胞也表达Ki67，这表明它们在样品收集时正在活跃地增殖。总之，这些数据揭示了CD4和CD8共受体的表达调节了TCR对脂质抗原的亲和力，导致功能多样性和M.tb疾病期间体内增殖的差异。