The TCR zeta-chain immunoreceptor tyrosine-based activation motifs are sufficient for the activation and differentiation of primary T lymphocytes.
The TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the gamma-, delta-, epsilon-, and zeta-chains. The need for this number of ITAMs is uncertain. Limited and contradictory studies have examined the ability of subsets of the TCR's ITAMs to signal into postthymic primary T lymphocytes. To study signaling by a restricted set of ITAMs, we expressed in transgenic mice a chimeric construct containing the IAs class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR zeta-chain. Tyrosine phosphorylation and receptor cocapping studies indicate that this chimeric receptor signals T cells independently of the remainder of the TCR. We show that CD4+ and CD8+ primary T cells, as well as naive and memory T cells, are fully responsive to stimulation through the IAs-zeta receptor. Further, IAs-zeta stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the zeta-chain ITAMs, in the absence of the gamma, delta, and epsilon ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the zeta-chain ITAMs in the development of surrogate TCRs for therapeutic purposes.
Geiger
T L
TL
Section of Immunobiology, and Department of Laboratory Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Leitenberg
D
D
Flavell
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism*
D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine