Camacho Iris A, Nagarkatti Mitzi, Nagarkatti Prakash S
Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Arch Toxicol. 2002 Oct;76(10):570-80. doi: 10.1007/s00204-002-0390-2. Epub 2002 Aug 6.
Immune response against a foreign antigen is characterized by a growth phase, in which antigen-specific T cells clonally expand, followed by a decline phase in which the activated T cells undergo apoptosis, a process termed activation-induced cell death (AICD). In the current study, we have investigated the phase at which 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) acts to downregulate the antigen-specific T cell response. To this end, C57BL/6 +/+ mice were injected with staphylococcal enterotoxin A (SEA) into the footpads (10 micro g/footpad), and simultaneously treated with TCDD (10 or 50 micro g/kg intraperitoneally). At various time points, the draining lymph node (LN) cells were analyzed for SEA-activated T cells. The data demonstrated that in C57BL/6 +/+ mice, TCDD treatment did not alter the growth phase but facilitated the decline phase of SEA-reactive T cells. TCDD caused a significant decrease in the percentage and absolute numbers of CD4(+) and CD8(+) SEA-responsive T cells expressing Vbeta3(+) and Vbeta11(+) but did not affect SEA-nonresponsive Vbeta8(+) T cells. Upon in vitro culture, TCDD-exposed SEA-immunized LN cells exhibited increased levels of apoptosis when compared with the vehicle controls. When Fas-deficient (C57BL/6 lpr/lpr) or Fas ligand defective (C57BL/6 gld/gld) mice were treated with TCDD, they failed to exhibit a decrease in percentage and cellularity of SEA-reactive T cells, thereby suggesting a role of Fas-Fas ligand interactions in the TCDD-induced downregulation of SEA-reactive T cell response. The resistance to TCDD-induced decrease in T cell responsiveness to SEA seen in Fas- and FasL-mutant mice was neither due to decreased aryl hydrocabon receptor (AhR) expression nor to altered T cell responsiveness to SEA. The current study demonstrates that TCDD does not prevent T cell activation, but prematurely induces Fas-based AICD, which may contribute to the deletion of antigen-primed T cells.
针对外来抗原的免疫反应具有一个生长阶段，在此阶段抗原特异性T细胞进行克隆性扩增，随后是一个衰退阶段，在此阶段活化的T细胞发生凋亡，这一过程称为活化诱导的细胞死亡（AICD）。在本研究中，我们调查了2,3,7,8-四氯二苯并 - p - 二恶英（TCDD）下调抗原特异性T细胞反应的作用阶段。为此，将C57BL/6 +/+小鼠脚垫注射金黄色葡萄球菌肠毒素A（SEA）（10微克/脚垫），并同时腹腔注射TCDD（10或50微克/千克）。在不同时间点，分析引流淋巴结（LN）细胞中的SEA活化T细胞。数据表明，在C57BL/6 +/+小鼠中，TCDD处理并未改变生长阶段，但促进了SEA反应性T细胞的衰退阶段。TCDD导致表达Vbeta3(+)和Vbeta11(+)的CD4(+)和CD8(+) SEA反应性T细胞的百分比和绝对数量显著下降，但不影响SEA无反应性的Vbeta8(+) T细胞。体外培养时，与载体对照相比，暴露于TCDD的SEA免疫的LN细胞凋亡水平增加。当用TCDD处理Fas缺陷（C57BL/6 lpr/lpr）或Fas配体缺陷（C57BL/6 gld/gld）小鼠时，它们未能表现出SEA反应性T细胞百分比和细胞数量的减少，从而表明Fas-Fas配体相互作用在TCDD诱导的SEA反应性T细胞反应下调中起作用。在Fas和FasL突变小鼠中观察到的对TCDD诱导的T细胞对SEA反应性降低的抗性，既不是由于芳烃受体（AhR）表达降低，也不是由于T细胞对SEA的反应性改变。本研究表明，TCDD不会阻止T细胞活化，但会过早诱导基于Fas的AICD,这可能有助于清除抗原致敏的T细胞。
