Zhang H G, Su X, Liu D, Liu W, Yang P, Wang Z, Edwards C K, Bluethmann H, Mountz J D, Zhou T
Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL 35294, USA.
J Immunol. 1999 Feb 1;162(3):1423-30.
Autocrine interaction of Fas and Fas ligand leads to apoptosis of activated T cells, a process that is critical for the maintenance of peripheral T cell tolerance. Paracrine interactions of Fas ligand with T cells also may play an important role in the maintenance of tolerance, as Fas ligand can create immune-privileged sites and prevent graft rejection by inducing apoptosis in T cells. We surmised that APCs that express Fas ligand might directly induce apoptosis of T cells during presentation of Ag to the T cells, thus inducing Ag-specific, systemic T cell tolerance. Here, we show that profound, specific T cell unresponsiveness to alloantigen was induced by treatment of H-2k mice with H-2b APCs that expressed Fas ligand and that profound T cell unresponsiveness specific for the H-Y Ag was induced by treatment of H-2Db/H-Y TCR transgenic female mice with H-2Db/H-Y APCs that expressed Fas ligand. The induction of this systemic T cell tolerance required the expression of Fas ligand on the APCs as well as the expression of Fas on the T cells. The tolerance was restricted to the Ag presented by the APCs. The rapid and profound clonal deletion of the Ag-specific, peripheral T cells mediated by the Fas ligand-expressing APCs contributed to the induction of tolerance. These findings demonstrate that Ag-specific T cell tolerance can be induced by APCs that express Fas ligand and suggest a novel function for APCs in the induction of T cell apoptosis. Furthermore, they indicate a novel immunointervention strategy for treatment of graft rejection and autoantigen-specific autoimmune diseases.
Fas与Fas配体的自分泌相互作用导致活化T细胞凋亡，这一过程对于维持外周T细胞耐受性至关重要。Fas配体与T细胞的旁分泌相互作用在维持耐受性方面也可能发挥重要作用，因为Fas配体可形成免疫赦免部位，并通过诱导T细胞凋亡来防止移植排斥。我们推测，表达Fas配体的抗原呈递细胞（APC）在向T细胞呈递抗原的过程中可能直接诱导T细胞凋亡，从而诱导抗原特异性的全身性T细胞耐受性。在此，我们表明，用表达Fas配体的H-2b APC处理H-2k小鼠可诱导对同种异体抗原产生深刻的、特异性的T细胞无反应性，并且用表达Fas配体的H-2Db/H-Y APC处理H-2Db/H-Y TCR转基因雌性小鼠可诱导对H-Y抗原产生深刻的、特异性的T细胞无反应性。这种全身性T细胞耐受性的诱导需要APC上Fas配体的表达以及T细胞上Fas的表达。耐受性仅限于APC呈递的抗原。由表达Fas配体的APC介导的抗原特异性外周T细胞的快速而深刻的克隆清除有助于耐受性的诱导。这些发现表明，表达Fas配体的APC可诱导抗原特异性T细胞耐受性，并提示APC在诱导T细胞凋亡方面具有新功能。此外，它们还表明了一种治疗移植排斥和自身抗原特异性自身免疫性疾病的新型免疫干预策略。
