Ali Mohamed, Weinreich Michael, Balcaitis Stephanie, Cooper Cristine J, Fink Pamela J
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
J Immunol. 2003 Dec 1;171(11):6290-6. doi: 10.4049/jimmunol.171.11.6290.
In Vbeta5 transgenic mice, mature Vbeta5(+)CD4(+) T cells are tolerized upon recognition of a self Ag, encoded by a defective endogenous retrovirus, whose expression is confined to the lymphoid periphery. Cells are driven by the tolerogen to enter one of two tolerance pathways, deletion or TCR revision. CD4(+) T cells entering the former pathway are rendered anergic and then eliminated. In contrast, TCR revision drives gene rearrangement at the endogenous TCR beta locus and results in the appearance of Vbeta5(-), endogenous Vbeta(+), CD4(+) T cells that are both self-tolerant and functional. An analysis of the molecules that influence each of these pathways was conducted to understand better the nature of the interactions that control tolerance induction in the lymphoid periphery. These studies reveal that deletion is efficient in reconstituted radiation chimeras and is B cell, CD28, inducible costimulatory molecule, Fas, CD4, and CD8 independent. In contrast, TCR revision is radiosensitive, B cell, CD28, and inducible costimulatory molecule dependent, Fas and CD4 influenced, and CD8 independent. Our data demonstrate the differential regulation of these two divergent tolerance pathways, despite the fact that they are both driven by the same tolerogen and restricted to mature CD4(+) T cells.
在Vbeta5转基因小鼠中，成熟的Vbeta5(+)CD4(+) T细胞在识别由缺陷型内源性逆转录病毒编码的自身抗原后会发生耐受，该逆转录病毒的表达局限于淋巴外周。细胞被耐受原驱动进入两条耐受途径之一，即缺失或TCR重排。进入前一条途径的CD4(+) T细胞会变得无反应性，然后被清除。相比之下，TCR重排在内源性TCR beta基因座驱动基因重排，导致出现Vbeta5(-)、内源性Vbeta(+)、既具有自身耐受性又有功能的CD4(+) T细胞。为了更好地理解控制淋巴外周耐受诱导的相互作用的本质，对影响这些途径的分子进行了分析。这些研究表明，在重建的辐射嵌合体中缺失是有效的，并且与B细胞、CD28、诱导性共刺激分子、Fas、CD4和CD8无关。相比之下，TCR重排对辐射敏感，依赖于B细胞、CD28和诱导性共刺激分子，受Fas和CD4影响，与CD8无关。我们的数据证明了这两条不同耐受途径的差异调节，尽管它们都是由相同的耐受原驱动且局限于成熟的CD4(+) T细胞。
