Development and function of T cells in T cell antigen receptor/CD3 zeta knockout mice reconstituted with Fc epsilon RI gamma
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1Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Howard Hughes Medical Institute, Denver, CO 80206, USA.
Abstract:
Engagement of alpha-beta T cell receptors (TCRs) induces many events in the T cells bearing them. The proteins that transduce these signals to the inside of cells are the TCR-associated CD3 polypeptides and zeta-zeta or zeta-eta dimers. Previous experiments using knockout (KO) mice that lacked zeta (zeta KO) showed that zeta is required for good surface expression of TCRs on almost all T cells and for normal T cell development. Surprisingly, however, in zeta KO mice, a subset of T cells 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 epsilon RI gamma (FcR gamma). These cells were relatively nonreactive to stimuli via their TCRs. In addition, a previous report showed that zeta 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 expressing FcR gamma in all of their T cells (FcR gamma TG zeta KO mice). In these mice, TCR expression on immature thymocytes was only slightly reduced compared with controls, and thymocyte selection occurred normally and gave rise to functional, mature T cells. Therefore, the nonreactivity of the FcR gamma + lymphocytes in the gut or in tumor-bearing mice must be caused by some other phenomenon. Unexpectedly, the TCR levels of mature T cells in FcR gamma TG zeta KO mice were lower than those of controls. This was particularly true for the CD4+ T cells. We conclude that FcR gamma can replace the functions of zeta in T cell development in vivo but that TCR/CD3 complexes associated with FcR gamma rather than zeta are less well expressed on cells. Also, these results revealed a difference in the regulation of expression of the TCR/CD3 complex on CD4+ and CD8+ T cells.
Insights
Fc receptor gamma (FcR gamma) can substitute for zeta chain in T cell receptor (TCR) development, but leads to lower TCR surface expression. This suggests alternative mechanisms cause T cell nonreactivity in certain conditions.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Alpha-beta T cell receptors (TCRs) signal into T cells via associated CD3 polypeptides and zeta-zeta or zeta-eta dimers.
- Previous studies showed zeta chain deficiency (zeta KO) impairs TCR surface expression and T cell development, though some T cells in zeta KO mice express TCRs via Fc receptor gamma (FcR gamma) but are nonreactive.
Purpose of the Study:
- To investigate the in vivo consequences of zeta chain substitution by FcR gamma on T cell development and function.
- To clarify the reasons for T cell nonreactivity observed in FcR gamma-expressing T cells.
Main Methods:
- Generation of zeta-deficient (zeta KO) mice expressing FcR gamma in all T cells (FcR gamma TG zeta KO mice).
- Analysis of TCR expression, T cell development, and thymocyte selection in FcR gamma TG zeta KO mice compared to controls.
Main Results:
- TCR expression on immature thymocytes was only slightly reduced in FcR gamma TG zeta KO mice, with normal thymocyte selection and development of functional T cells.
- Mature T cells in FcR gamma TG zeta KO mice exhibited lower TCR levels than controls, particularly CD4+ T cells.
- The nonreactivity of FcR gamma-positive T cells in gut or tumor-bearing mice is not due to impaired development but likely another phenomenon.
Conclusions:
- FcR gamma can functionally replace the zeta chain in T cell development in vivo.
- TCR/CD3 complexes associated with FcR gamma are less well expressed on T cells compared to those with zeta.
- Distinct regulation of TCR/CD3 complex expression exists between CD4+ and CD8+ T cells.