The CD3 γϵ/δϵ signaling module provides normal T cell functions in the absence of the TCR ζ immunoreceptor tyrosine‐based activation motifs

Center for Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
European Journal of Immunology (Impact Factor: 4.03). 01/2006; 35(12):3643-54. DOI: 10.1002/eji.200535136
Source: PubMed


T cell receptor (TCR) signal transduction is mediated by the immunoreceptor tyrosine-based activation motifs (ITAM). The ten ITAM in the TCR complex are distributed in two distinct signaling modules termed TCR zetazeta and CD3 gammaepsilon/deltaepsilon. To delineate the specific role of the zeta ITAM in T cell development and TCR signal transmission, we compared the properties of T cells from different TCR zeta-transgenic lines wherein tyrosine-to-phenylalanine substitutions had been introduced in the zeta subunit. These lines lack selected phosphorylated forms of TCR zeta including just p23, both p21 and p23, or all phospho-zeta derivatives. We report herein that the efficiency of positive selection in HY TCR-transgenic female mice was directly related to the number of zeta ITAM in the TCR. In contrast, TCR-mediated signal transmission and T cell proliferative responses following agonist peptide stimulation were similar and independent of the zeta ITAM. Only the duration of MAPK activation was affected by multiple zeta ITAM substitutions. These results strongly suggest that the ITAM in the CD3 gammaepsilon/deltaepsilon module can provide normal TCR signal transmission, with zeta ITAM providing a secondary function facilitating MAPK activation and positive selection.

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Available from: Christoph Wuelfing, Dec 11, 2014
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    • "It was recently reported that attenuation of TCR-proximal signaling by inactivation of the TCR chain immunoreceptor tyrosine based activation motifs (ITAMs) in mice results in a selective defect in negative selection that leads to a rapidly progressive, fatal, multi-system autoimmune disease (Holst et al., 2008). However, these findings contrast with previous data indicating that although attenuation of TCR signaling potential impairs negative selection it does not cause autoimmune disease (Shores et al., 1997; Ardouin et al., 1999; Pitcher et al., 2005b). As these results have important conceptual and clinical implications, further investigation aimed at resolving this discrepancy is warranted. "
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    Journal of Experimental Medicine 09/2012; 209(10):1781-95. DOI:10.1084/jem.20120058 · 12.52 Impact Factor
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    • "A total of 10 ITAMs are distributed in the TCR/CD3 complex in two distinct signaling modules termed the TCRζζ and CD3γε/δε [24,25]. Although the TCRζζ ITAM plays a central role in TCR signal transmission, the CD3γε/δε ITAM module can provide normal TCR signal transmission in the absence of a TCRζζ ITAM motif [26]. To gain more insight into TCR signal transduction, which is important for T cells activation, we analyzed the expression level of all four CD3 genes (i.e., CD3γ, CD3δ, CD3ε and CD3ζ) and the CD3ζ-related FcεRIγ gene in PBMCs from patients with AA. "
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    • "Autoimmunity is observed when two to six ITAMs are expressed ITAM-mediated Signaling by the T-Cell Antigen Receptor Cite this article as Cold Spring Harb Perspect Biol 2010;2:a002485 peptides (Hogquist et al. 1994; Santori et al. 2002) indicating that amplification of TCR signals generated from such interactions may be especially important for positive selection. Consistent with this notion, positive selection was found to be markedly impaired in zdeficient mice reconstituted with transgenes encoding ITAM mutant z chains (Shores et al. 1994; Ardouin et al. 1999; Pitcher et al. 2005b). Moreover, in each of these model systems, the extent to which positive selection was compromised was directly related to the number of z ITAMs that had been deleted or inactivated. "
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