DEVELOPMENT AND FUNCTION OF T-CELL IN T-CELL ANTIGEN RECEPTOR CD3-ZETA KNOCKOUT MICE RECONSTITUTED WITH FC-EPSILON-RI-GAMMA

Engagement of alpha-beta T cell receptors (TCRs) induces many events i n the T cells bearing them. The proteins that transduce these signals to the inside of cells are the TCR-associated CD3 polypeptides and zet a-zeta or zeta-eta dimers. Previous experiments using knockout (KO) mi ce that lacked zeta (zeta KO) showed that zeta is required for good su rface expression of TCRs on almost all T cells and for normal T cell d evelopment. Surprisingly, however, in zeta KO mice, a subset of T cell s in the gut of both zeta KO and normal mice bore nearly normal levels of TCR on its surface. This was because zeta was replaced by the Fc e psilon RI gamma (FcR gamma). These cells were relatively nonreactive t o stimuli via their TCRs, In addition, a previous report showed that z eta replacement by the FcR gamma chain also might occur on T cells in mice bearing tumors long term. Again, these T cells were nonreactive. To understand the consequences of zeta substitution by FcR gamma for T cell development and function in vivo, we produced zeta KO mice expre ssing FcR gamma in all of their T cells (FcR gamma TG zeta KO mice). I n these mice, TCR expression on immature thymocytes was only slightly reduced compared with controls, and thymocyte selection occurred norma lly and gave rise to functional, mature T cells. Therefore, the nonrea ctivity of the FcR gamma(+) lymphocytes in the gut or in tumor-bearing mice must be caused by some other phenomenon. Unexpectedly, the TCR l evels of mature T cells in FcR gamma TG zeta KO mice were lower than t hose of controls. This was particularly true for the CD4(+) T cells. W e conclude that FcR gamma can replace the functions of zeta in T cell development in vivo but that TCR/CD3 complexes associated with FcR gam ma rather than zeta are less well expressed on cells, Also, these resu lts revealed a difference in the regulation of expression of the TCR/C D3 complex on CD4(+) and CD8(+) T cells.