Different role for mouse and human CD3δ/ɛ heterodimer in preT cell receptor (preTCR) function: Human CD3δ/ɛ heterodimer restores the defective preTCR function in CD3γ- and CD3γδ-deficient mice

The majority of T cell receptor (TCR) complexes in mice and humans consist of a heterodimer of polymorphic TCRα and β chains along with invariant CD3γ, δ, ɛ, and ζ chains. CD3 chains are present as CD3γɛ, δɛ, and ζζ dimers in the receptor complex and play critical roles in the antigen receptor assembly, transport to the cell surface, and the receptor-mediated signal transduction. That CD3 chains play critical roles in thymocyte development is apparent from the analyses of CD3 deficient mice. PreT cell receptor (preTCR)-mediated CD4−CD8− (double negative or DN) to CD4+CD8+ (double positive or DP) transition is severely impaired in mice deficient in either CD3γ, or ɛ, or ζ chain. In contrast, CD3δ deficiency impairs thymocyte maturation at the CD4+CD8+ double positive (DP) stage suggesting that CD3δ is not required for the preTCR-mediated DN to DP transition. However, recent data suggest that a defect in human CD3δ results in impaired development at the DN stage indicating a role for hCD3δ in preTCR-mediated DN to DP transition. To determine if human CD3δ/ɛ (hCD3δ/ɛ) could mediate preTCR-mediated DN to DP transition, we employed a human CD3 transgene that encodes full length CD3δ and a truncated but functional form of CD3ɛ. Surprisingly, the transgene restored the defective preTCR function in not only CD3ɛ- but CD3γ- and CD3γδ-deficient mice as well. A possible role for human CD3δ/ɛ heterodimer in the preTCR-mediated DN to DP transition is discussed.