Reversal of the T cell immune system reveals the molecular basis for T cell lineage fate determination in the thymus

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 byCd4andCd8gene 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 byCd4, but promote the cytotoxic-lineage fate when encoded inCd8—regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined bycis-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 thatCd4andCd8gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.