NEONATAL T-CELL TOLERANCE TO MINIMAL IMMUNOGENIC PEPTIDES IS CAUSED BY CLONAL INACTIVATION
NEONATAL T-CELL TOLERANCE TO MINIMAL IMMUNOGENIC PEPTIDES IS CAUSED BY CLONAL INACTIVATION
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DOI：
10.1038/319413a0
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发表时间：
1986-01-30
期刊：
影响因子：
64.8
通讯作者：
SERCARZ, EE
中科院分区：
文献类型：
--
作者：
GAMMON, G;DUNN, K;SERCARZ, EE
诱导新生小鼠T淋巴细胞耐受的机制尚不清楚1-3。目前尚不清楚这种耐受状态是T细胞在发育过程中暴露于抗原时失活的结果，还是被其他针对同一抗原的T细胞主动抑制的结果。为了区分这两种假设，我们分析了对三种细胞色素多肽的耐受性，这些细胞色素多肽在增殖T细胞识别的表位上只有一个氨基酸替换。这些多肽刺激增殖反应，具有高度的特异性和最小的交叉反应。由于抗原诱导的克隆性失活将针对通常由该抗原激活的相同细胞，因此耐受的特异性应该与对该抗原的增殖反应的特异性完全匹配，并且每个细胞色素多肽都应该单独诱导对其自身的耐受。相反，由于T抑制(TS)和T增殖(TP)细胞似乎几乎总是识别蛋白质抗原上不同的、不重叠的决定因素(例如，见参考文献4-6)，抑制因子介导的耐受不应受到增殖T细胞表位替换的影响。耐受性仅取决于是否存在共同的抑制子决定簇，因此每个细胞色素多肽都应该诱导对其他细胞色素多肽的交叉耐受。我们发现，耐受性的特异性与增殖反应相匹配：每种多肽都能诱导自身的耐受性，但对变异体的反应没有改变。这一结果有力地支持了克隆失活是诱导新生儿耐受的重要机制的假说。
The mechanisms underlying T-lymphocyte tolerance induced in neonatal mice are still unknown1–3. It is unclear whether the tolerant state is the result of inactivation of T cells on exposure to antigen during development or of active suppression by other T cells specific for the same antigen. To distinguish between these two hypotheses, we have analysed the specificity of tolerance to three cytochrome peptides which differ by only a single amino-acid substitution in the epitope recognized by proliferative T cells. The peptides stimulate proliferative responses which are highly specific with minimal cross-reactivity. As antigen-induced clonal inactivation would address the same cells normally activated by that antigen, the specificity of tolerance should exactly match that of the proliferative response to the antigen, and each cytochrome peptide should induce tolerance to itself alone. Conversely, as T-suppressor (Ts) and T-proliferative (Tp) cells almost invariably seem to recognize distinct, non-overlapping determinants on protein antigens (see, for example, refs 4–6), suppressor-mediated tolerance should not be affected by substitutions in the proliferative T-cell epitope. Tolerance would depend solely on the existence of a shared suppressor determinant, so each cytochrome peptide should induce cross-tolerance to the others. We found that the specificity of tolerance matched that of the proliferative response: each peptide induced tolerance for itself but the response to the variants was unaltered. This result strongly supports the hypothesis of clonal inactivation as an important mechanism in induction of neonatal tolerance.