Pacholczyk Rafal, Kraj Piotr, Ignatowicz Leszek
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
J Immunol. 2002 Jan 15;168(2):613-20. doi: 10.4049/jimmunol.168.2.613.
The CD4(+)CD25(+) regulatory T cells can be found in the thymus, but their need to undergo positive and negative selection has been questioned. Instead, it has been hypothesized that CD4(+)CD25(+) cells mature following TCR binding to MHC backbone, to low abundant MHC/peptide complexes, or to class II MHC loaded with peripheral autoantigens. In all these circumstances, processes that are distinct from positive and negative selection would govern the provenance of CD4(+)CD25(+) cells in the thymus. By comparing the development of CD4(+)CD25(-) and CD4(+)CD25(+) cells in mice expressing class II MHC molecules bound with one or many peptide(s), we show that the CD4(+)CD25(+) cells appear during natural selection of CD4(+) T cells. The proportion of CD4(+)CD25(+) cells in the population of CD4(+) thymocytes remains constant, and their total number reflects the complexity of selecting class II MHC/peptide complexes. Hence, thymic development of CD4(+)CD25(+) cells does not exclusively depend on the low-density, high-affinity MHC/peptide complexes or thymic presentation of peripheral self-Ags, but, rather, these cells are selected as a portion of the natural repertoire of CD4(+) T cells. Furthermore, while resistant to deletion mediated by endogenous superantigen(s), these cells were negatively selected on class II MHC/peptide complexes. We postulate that while the CD4(+)CD25(+) thymocytes are first detectable in the thymic medulla, their functional commitment occurs in the thymic cortex.
CD4(+)CD25(+)调节性T细胞可在胸腺中发现，但其是否需要经历阳性和阴性选择一直存在疑问。相反，有人提出假设，CD4(+)CD25(+)细胞在TCR与MHC骨架、低丰度MHC/肽复合物或负载外周自身抗原的II类MHC结合后成熟。在所有这些情况下，与阳性和阴性选择不同的过程将决定胸腺中CD4(+)CD25(+)细胞的来源。通过比较在表达与一种或多种肽结合的II类MHC分子的小鼠中CD4(+)CD25(-)和CD4(+)CD25(+)细胞的发育情况，我们发现CD4(+)CD25(+)细胞出现在CD4(+)T细胞的自然选择过程中。CD4(+)胸腺细胞群体中CD4(+)CD25(+)细胞的比例保持恒定，其总数反映了选择II类MHC/肽复合物的复杂性。因此，CD4(+)CD25(+)细胞的胸腺发育并不完全依赖于低密度、高亲和力的MHC/肽复合物或外周自身抗原的胸腺呈递，相反，这些细胞是作为CD4(+)T细胞自然库的一部分被选择的。此外，虽然这些细胞对内源性超抗原介导的缺失具有抗性，但它们在II类MHC/肽复合物上被阴性选择。我们推测，虽然CD4(+)CD25(+)胸腺细胞首先在胸腺髓质中可检测到，但其功能承诺发生在胸腺皮质中。
