Leitner Judith, Herndler-Brandstetter Dietmar, Zlabinger Gerhard J, Grubeck-Loebenstein Beatrix, Steinberger Peter
Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria; and.
J Immunol. 2015 Jul 15;195(2):477-87. doi: 10.4049/jimmunol.1401917. Epub 2015 Jun 3.
A substantial proportion of CD8(+) T cells in adults lack the expression of the CD28 molecule, and the aging of the immune system is associated with a steady expansion of this T cell subset. CD28(-)CD8(+) T cells are characterized by potent effector functions but impaired responses to antigenic challenge. CD28 acts as the primary T cell costimulatory receptor, but there are numerous additional receptors that can costimulate the activation of T cells. In this study, we have examined such alternative costimulatory pathways regarding their functional role in CD28(-)CD8(+) T cells. Our study showed that most costimulatory molecules have a low capacity to activate CD28-deficient T cells, whereas the engagement of the CD2 molecule by its ligand CD58 clearly costimulated proliferation, cytokine production, and effector function in this T cell subset. CD58 is broadly expressed on APCs including dendritic cells. Blocking CD58 mAb greatly reduced the response of human CD28(-)CD8(+) T cells to allogeneic dendritic cells, as well as to viral Ags. Our results clearly identify the CD58/CD2 axis as the primary costimulatory pathway for CD8 T cells that lack CD28. Moreover, we show that engagement of CD2 amplifies TCR signals in CD28(-)CD8(+) T cells, demonstrating that the CD2-CD58 interaction has a genuine costimulatory effect on this T cell subset. CD2 signals might promote the control of viral infection by CD28(-)CD8(+) T cells, but they might also contribute to the continuous expansion of CD28(-)CD8(+) T cells during chronic stimulation by persistent Ag.
在成年人中，相当一部分CD8(+) T细胞缺乏CD28分子的表达，而免疫系统的老化与这一T细胞亚群的持续扩增有关。CD28(-)CD8(+) T细胞具有强大的效应功能，但对抗抗原刺激的反应受损。CD28作为主要的T细胞共刺激受体，但还有许多其他受体可以共刺激T细胞的活化。在本研究中，我们研究了这些替代共刺激途径在CD28(-)CD8(+) T细胞中的功能作用。我们的研究表明，大多数共刺激分子激活CD28缺陷型T细胞的能力较低，而其配体CD58与CD2分子的结合明显共刺激了该T细胞亚群的增殖、细胞因子产生和效应功能。CD58广泛表达于包括树突状细胞在内的抗原呈递细胞上。阻断CD58单克隆抗体可大大降低人CD28(-)CD8(+) T细胞对同种异体树突状细胞以及病毒抗原的反应。我们的结果清楚地确定CD58/CD2轴是缺乏CD28的CD8 T细胞的主要共刺激途径。此外，我们表明CD2的结合可放大CD28(-)CD8(+) T细胞中的TCR信号，证明CD2 - CD58相互作用对该T细胞亚群具有真正的共刺激作用。CD2信号可能促进CD28(-)CD8(+) T细胞对病毒感染的控制，但它们也可能在持续抗原的慢性刺激过程中导致CD28(-)CD8(+) T细胞的持续扩增。
