Generation of antigen-specific cytotoxic T lymphocytes and regulation of cytokine production takes place in the absence of CD3 zeta

The TCR-associated protein CD3 zeta plays a major role in regulating the st ate of responsiveness to peptide-MHC complexes on the surface of antigen-pr esenting cells, In this paper the requirement of CD3 zeta in the generation of cytotoxic T cells was compared with its requirement in cytokine gene ac tivation in two mutant mice: ZKO mice with a disrupted CD3 zeta gene and ZT G mice in which a truncated CD3 zeta segment was expressed as a transgene o n the ZKO background, Upon infection of ZTG mice with lymphocytic choriomen ingitis virus (LCMV), antigen-specific cytotoxic T lymphocyte (CTL) respons es were detected, identical to responses in wild-type mice, In addition, an tigen-specific CTL responses to allogeneic class I and class II MHC in ZTG animals were indistinguishable from those in wild-type animals, However, CT L responses to the same major antigens were not detectable in ZKO mice, We conclude that the signal transduction pathways leading to CTL development a nd cytokine production can be triggered through TCR in the absence of funct ional CD3 zeta, provided the remainder of the TCR-CD3 complex is expressed at high levels on the cell surface. Surprisingly, IFN-gamma production in r esponse to LCMV followed the same kinetics in ZKO, ZTG and wild-type mice, However, in vitro studies showed that cytokine production in general was ab normally regulated in T lymphocytes from ZKO mice, in contrast to ZTG T cel ls, Taken together, these studies support the hypothesis that development o f CTL can take place in the absence of functional CD3 zeta;, However, CTL d evelopment requires stronger TCR-initiated signal transduction events than induction of cytokine genes.