T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8—regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.

T 细胞特异性和功能在发育过程中相互关联，因为 MHC-II 特异性 TCR 信号生成 CD4 辅助 T 细胞，而 MHC-I 特异性 TCR 信号生成 CD8 细胞毒性 T 细胞，但其基础仍不确定。我们现在报道，转换由Cd4和Cd8基因位点编码的辅助受体蛋白可在功能上逆转 T 细胞免疫系统，产生 CD4 细胞毒性和 CD8 辅助 T 细胞。这种功能逆转揭示了辅助受体蛋白在由Cd4编码时促进辅助谱系命运，但在由Cd8编码时促进细胞毒性谱系命运——无论每个位点编码的辅助受体蛋白是什么。因此，T细胞谱系命运是由辅助受体基因位点中的顺式调节元件决定的，而不是由它们编码的辅助受体蛋白决定的，从而使辅助受体信号强度作为谱系命运决定的基础无效。此外，我们认为进化选择了Cd4和Cd8基因位点编码的特定辅助受体蛋白，以避免产生功能逆转的 T 细胞，因为它们无法促进针对环境病原体的保护性免疫。