Laboratory of Molecular Immunology, Blood Research Institute, Milwaukee, Wisconsin, United States of America.
PLoS One. 2010 Sep 9;5(9):e12635. doi: 10.1371/journal.pone.0012635.
Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived naïve (CD45RA+CD27+) and memory (CD45RA-CD27+) CD8+ T cells (CD28Hi), while its expression was significantly lower in effector (CD45RA+CD27-) CD8+ T cells (CD28Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naïve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate naïve CD8+ T cells would require CD28-mediated co-stimulation.
CD28 和 NKG2D 均可作为人类 CD8+T 细胞的共刺激受体发挥作用。然而，它们在不同的 CD8+T 细胞亚群中的独立功能贡献尚不清楚。在这项研究中，我们分析了人外周血和肺衍生淋巴细胞中的 CD8+T 细胞的 CD28 和 NKG2D 的表达和功能。我们发现，外周血单核细胞衍生的幼稚（CD45RA+CD27+）和记忆（CD45RA-CD27+）CD8+T 细胞（CD28Hi）中 CD28 的表达水平较高，而效应（CD45RA+CD27-）CD8+T 细胞（CD28Lo）中的表达水平则显著较低。无论 CD28 水平的差异如何，所有三种 CD8+T 细胞亚群中的 NKG2D 表达水平都相当。CD28 和 NKG2D 的表达在人类肺驻留 GILGFVFTL/HLA-A2-五聚体阳性 CD8+T 细胞中呈现相似的模式。通过 NKG2D 共刺激 CD28Lo 效应 T 细胞可显著增加 IFN-γ 和 TNF-α水平。相反，无论其表达水平相当，NKG2D 介导的共刺激都不能增强 CD28Hi 幼稚/记忆 T 细胞中 IFN-γ 和 TNF-α的产生。此外，CD28 介导的共刺激对于 IL-2 的产生是必需的，因此其产生仅限于 CD28Hi 幼稚/记忆亚群。NKG2D 的配体 MICA 在气管上皮细胞中大量表达，证实了组织驻留的 CD8+效应 T 细胞主要利用 NKG2D 作为共刺激受体。基于这些发现，我们得出结论，NKG2D 可能为组织驻留的效应 CD8+T 细胞提供扩展水平的共刺激。因此，除了 CD28 之外，通过 NKG2D 加入共刺激对于激活肿瘤或组织浸润的效应 CD8+T 细胞是必不可少的。然而，通过记忆 CD8+T 细胞增强回忆免疫应答或通过疫苗刺激幼稚 CD8+T 细胞需要 CD28 介导的共刺激。
