Maile Robert, Siler Catherine A, Kerry Samantha E, Midkiff Katherine E, Collins Edward J, Frelinger Jeffrey A
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA.
J Immunol. 2005 Jan 15;174(2):619-27. doi: 10.4049/jimmunol.174.2.619.
In this study, we suggest that CD8 levels on T cells are not static, but can change and, as a result, modulate CD8(+) T cell responses. We describe three models of CD8 modulation using novel weak-agonist (K1A) and super-agonist (C2A) altered peptide ligands of the HY smcy peptide. First, we used peripheral nonresponsive CD8(low) T cells produced after peripheral HY-D(b) MHC class I tetramer stimulation of female HY TCR transgenic and wild-type mice. Second, we used genetically lowered CD8(int) T cells from heterozygote CD8(+/0) mice. Finally, we used pre-existing nonresponsive CD8(low) T cells from male HY TCR transgenic mice. In CD8(low) and CD8(high) mice, presence of a lower level of CD8 greatly decreased the avidity of the peptide-MHC for HY TCR as reflected by avidity (K(D)) and dissociation constant (T(1/2)) measurements. All three models demonstrated that lowering CD8 levels resulted in the requirement for a higher avidity peptide-MHC interaction with the TCR to respond equivalently to unmanipulated CD8(high) T cells of the same specificity. Additionally, direct injections of wild-type HY-D(b) and C2A-D(b) tetramers into female HY TCR or female B6 mice induced a high frequency of peripheral nonresponsive CD8(low) T cells, yet C2A-D(b) was superior in inducing a primed CD8(+)CD44(+) memory population. The ability to dynamically modulate the size and responsiveness of an Ag-specific T cell pool by "CD8 tuning" of the T cell during the early phases of an immune response has important implications for the balance of responsiveness, memory, and tolerance.
在本研究中，我们认为T细胞上的CD8水平并非一成不变，而是可以发生变化，进而调节CD8⁺ T细胞反应。我们使用新型弱激动剂（K1A）和超激动剂（C2A）修饰的HY smcy肽配体，描述了三种CD8调节模型。首先，我们使用雌性HY TCR转基因和野生型小鼠经外周HY-D(b) MHC I类四聚体刺激后产生的外周无反应性CD8(low) T细胞。其次，我们使用来自杂合子CD8(+/0)小鼠的基因敲低的CD8(int) T细胞。最后，我们使用雄性HY TCR转基因小鼠中预先存在的无反应性CD8(low) T细胞。在CD8(low)和CD8(high)小鼠中，较低水平CD8的存在显著降低了肽-MHC与HY TCR的亲和力，这通过亲和力（K(D)）和解离常数（T(1/2)）测量得以体现。所有这三种模型均表明，降低CD8水平导致需要更高亲和力的肽-MHC与TCR相互作用，才能与相同特异性的未处理CD8(high) T细胞产生等效反应。此外，将野生型HY-D(b)和C2A-D(b)四聚体直接注射到雌性HY TCR或雌性B6小鼠中，诱导产生了高频的外周无反应性CD8(low) T细胞，但C2A-D(b)在诱导初始CD8⁺CD44⁺记忆群体方面更具优势。在免疫反应早期通过对T细胞进行“CD8调节”来动态调节抗原特异性T细胞库的大小和反应性，对反应性、记忆和耐受性的平衡具有重要意义。
