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as an Amplifier of Low-Avidity TCR Signaling1
* Julia McFarlane Diabetes Research Centre and Departments of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada;
Departments of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada;
Department of Internal and Geriatric Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan; and
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105
Engagement of peptide-MHC by the TCR induces a conformational change in CD3
that exposes a proline-rich sequence (PRS) and recruits the cytoskeletal adaptor Nck. This event, which precedes phosphorylation of the CD3 ITAM, has been implicated in synapse formation and T cell function. However, there is compelling evidence that responsiveness to TCR ligation is CD3 PRS independent. In this study, we show that the CD3 PRS is necessary for peptide-MHC-induced phosphorylation of CD3 and for recruitment of protein kinase C
to the immune synapse in differentiated CD8+ T lymphocytes. However, whereas these two events are dispensable for functional T cell responsiveness to high-avidity ligands, they are required for responsiveness to low-avidity ones. Thus, in at least certain T cell clonotypes, the CD3 PRS amplifies weak TCR signals by promoting synapse formation and CD3 phosphorylation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Natural Sciences and Engineering Research Council of Canada and by a Core Facility supported by a Group Grant from the Canadian Institutes for Health Research. S.T., A.S., and P.Se. were supported by studentships from the Alberta Heritage Foundation for Medical Research (AHFMR). A.L.S.-W. and D.A.A.V. were supported by the National Institutes of Health (AI52199), the St. Jude Cancer Center Support Center of Research Excellence Grant CA-21765, and the American Lebanese Syrian Associated Charities. P.Sa. and S.R. are Scientists of the AHFMR. The JMDRC is supported by the Diabetes Association (Foothills).
2 Address correspondence and reprint requests to Dr. Pere Santamaria, Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada. E-mail address: psantama{at}ucalgary.ca
3 Abbreviations used in this paper: pMHC, peptide-MHC; LAT, linker for activation of T cells; SH2, Src homology 2; SLP, SH2 domain-containing leukocyte protein; PRS, proline-rich sequence; PKC, protein kinase C; DC, dendritic cell; RT, room temperature; eGFP, enhanced GFP; POPLN, popliteal lymph node; MLN, mesenteric lymph node; PLN, pancreatic lymph node; SH3, Src homology 3.
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