PREFERENTIAL REQUIREMENT OF CD3-ZETA-MEDIATED SIGNALS FOR DEVELOPMENTOF IMMATURE RATHER THAN MATURE THYMOCYTES

Antigen recognition signals by the TCR are transduced through activati on motifs present in the cytoplasmic region of CD3 chains. In vitro an alysis has suggested that the CD3 zeta chain mediates different signal s from other CD3 chains. To analyze the in vivo function of CD3 zeta-m ediated signals for T cell development, mice expressing a mutant CD3 z eta chain lacking all the activation motifs were generated by introduc ing the transgene into zeta-knockout mice. Mature CD4(+) single-positi ve (SP) thymocytes in these mice were greater in number than in zeta-d eficient mice, and the promoted differentiation was indicated by the c hanges of CD69 and HSA phenotypes. We found that even in the absence o f activation motifs in CD3 zeta, these mature cells became functional, being able to induce Ca2+ mobilization and proliferation upon stimula tion. On the other hand, CD4(-)CD8(-) double-negative (DN) thymocytes, most of which were arrested at the CD44(-)CD25(+) stage similarly to those in zeta-deficient mice, could not be promoted for differentiatio n into CD(4+)CD8(+) double-positive thymocytes in these mice in spite of the fact that the expression of the transgene in DN thymocytes was higher than that of zeta in wild-type mice. These results demonstrate the preferential dependence of the promotion of development and/or exp ansion of DN thymocytes rather than mature thymocytes upon the activat ion signals through the zeta chain and suggest differential requiremen ts of TCR signaling for mature SP and immature DN thymocyte developmen ts in vivo.