Zelenay Santiago, Bergman Marie-Louise, Paiva Ricardo Sousa, Lino Andreia C, Martins Ana C, Duarte João H, Moraes-Fontes Maria F, Bilate Angelina M, Lafaille Juan J, Demengeot Jocelyne
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
J Immunol. 2010 Oct 1;185(7):3829-33. doi: 10.4049/jimmunol.1001281. Epub 2010 Sep 3.
Thymocytes differentiate into CD4(+) Foxp3(+) regulatory T cells (T(R)) upon interaction between their TCR and peptide-MHC II complexes locally expressed in the thymus. Conversion of naive CD4(+) T cells into T(R) can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3(+) cells, we report de novo generation of T(R) upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt T(R) differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4(+) T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for T(R) generation with major implications for immunity and tolerance induction.
胸腺细胞在其TCR与胸腺局部表达的肽 - MHC II复合物相互作用后，分化为CD4(+) Foxp3(+)调节性T细胞（T(R)）。在抗原接触的非炎症条件下，外周幼稚CD4(+) T细胞也可额外转化为T(R)。在本研究中，利用天然缺乏Foxp3(+)细胞的TCR转基因模型，我们报告了在单次足垫注射与经典促炎佐剂混合的抗原后，T(R)的从头生成。免疫后T(R)的突然分化发生在胸腺内，并且对于自发脑脊髓炎小鼠模型中强大的耐受性诱导至关重要。这种现象可归因于胸腺细胞的一个特定特征，与成熟外周CD4(+) T细胞相比，胸腺细胞对IL - 6对Foxp3表达诱导的抑制作用不敏感。我们的发现揭示了一条T(R)生成途径，对免疫和耐受性诱导具有重要意义。
