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Otto-von-Guericke University, Institute of Molecular and Clinical Immunology, Magdeburg, Germany
The transmembrane adaptor protein SIT is a negative regulator of TCR-mediated signaling. However, little is known about the functional role of SIT in mature T cells. In this study, we show that mice deficient for SIT display a decreased number of naive CD8+ T cells and a progressive accumulation of memory-like (CD44high) CD8+ T lymphocytes that resemble cells undergoing homeostatic proliferation. Indeed, when transferred into lymphopenic hosts, SIT–/– naive CD8+ T cells undergo enhanced homeostatic proliferation and express a higher level of CD44 in comparison to wild-type T cells. By using class-I-restricted TCR transgenic models with different ligand affinity/avidity, we show that lymphopenia-induced homeostatic proliferation is more pronounced in cells carrying low-affinity TCRs. Strikingly, the loss of SIT induces homeostatic proliferation of HY TCR transgenic cells, which are normally unable to proliferate in lymphopenic mice. Collectively, these data demonstrate that SIT negatively regulates T cell homeostasis. Finally, we show that SIT-deficient T cells develop a mechanism analogous to sensory adaptation as they up-regulate CD5, down-regulate the coreceptor, and display impaired TCR-mediated ZAP-70 activation.
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 Deutsche Forschungsgemeinschaft Grant FOR521, SI 861/1 and GRK-1167, and by the German Ministry of Education and Research (Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie) Grant 01ZZ0407 NBL3-2.
2 Address correspondence and reprint requests to Dr. Luca Simeoni, Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail address: luca.simeoni{at}med.ovgu.de
3 Abbreviations used in this paper: SIT, Src homology domain containing tyrosine phosphatase 2-interacting transmembrane adaptor protein; LAT, linker for activation of T cells; WT, wild type; BTLA, B and T lymphocyte attenuator.
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