Schwarz A, Grabbe S, Grosse-Heitmeyer K, Roters B, Riemann H, Luger T A, Trinchieri G, Schwarz T
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University Münster, Germany.
J Immunol. 1998 May 1;160(9):4262-70.
Hapten sensitization through UV-exposed skin induces tolerance that is mediated via the induction of hapten-specific T suppressor cells. However, the detailed mechanisms underlying tolerance induction remain unclear to date. We show here that the apoptosis-related surface Ag Fas (APO-1, CD95) and its ligand, Fas ligand (FasL) are critically involved, since Fas-deficient lpr mice and FasL-deficient gld mice do not develop UV-induced tolerance. Adoptive transfer experiments revealed that the mediation of tolerance does not require the expression of Fas or FasL by the T suppressor cells but does require the expression of both molecules by the cells of mice receiving the T suppressor cells. To identify the mechanisms involved, the effect of suppressor cells on Ag-presenting dendritic cells (DC) was studied. Coincubation of hapten-pulsed DC with T cells that were obtained from UV-tolerized mice resulted in an enhanced death rate of DC, and this cell death was dependent upon Fas expression. The addition of IL-12, which recently was found to break established tolerance in vivo, prevented DC death. Moreover, IL-12 did not only rescue DC from T suppressor cell-induced death but also from apoptosis induced by rFasL, suggesting that IL-12 may interfere with the Fas/FasL system. Together, these data indicate a crucial role for the Fas/FasL system in UV-induced tolerance, and suggest that UV-induced T suppressor cells may act by inducing the cell death of APCs via the Fas pathway. The ability of IL-12 to break established tolerance may be due to the prevention of DC death induced by T suppressor cells.
通过紫外线照射皮肤进行的半抗原致敏可诱导耐受性，这种耐受性是由半抗原特异性T抑制细胞的诱导介导的。然而，迄今为止，耐受性诱导的详细机制仍不清楚。我们在此表明，凋亡相关表面抗原Fas（APO-1，CD95）及其配体Fas配体（FasL）至关重要，因为Fas缺陷的lpr小鼠和FasL缺陷的gld小鼠不会产生紫外线诱导的耐受性。过继转移实验表明，耐受性的介导不需要T抑制细胞表达Fas或FasL，但确实需要接受T抑制细胞的小鼠细胞同时表达这两种分子。为了确定其中涉及的机制，研究了抑制细胞对半抗原呈递树突状细胞（DC）的影响。将半抗原脉冲的DC与从紫外线耐受小鼠获得的T细胞共同孵育，导致DC的死亡率增加，并且这种细胞死亡依赖于Fas表达。添加最近发现可在体内打破已建立的耐受性的IL-12可防止DC死亡。此外，IL-12不仅可使DC从T抑制细胞诱导的死亡中获救，还可使其从rFasL诱导的凋亡中获救，这表明IL-12可能会干扰Fas/FasL系统。总之，这些数据表明Fas/FasL系统在紫外线诱导的耐受性中起关键作用，并表明紫外线诱导的T抑制细胞可能通过Fas途径诱导APC细胞死亡来发挥作用。IL-12打破已建立的耐受性的能力可能是由于防止了T抑制细胞诱导的DC死亡。
