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The Transmembrane Adapter Protein SIT Regulates Thymic Development and Peripheral T-Cell Functions

Otto von Guericke University, Institute of Immunology, Leipziger Str. 44, 39120 Magdeburg, Germany,¹ FOCUS Clinical Drug Development GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany,² Heinrich Heine University, Institute of Medical Microbiology, Universitäts Str. 1, 40225 Düsseldorf, Germany³

Received 21 December 2004/ Returned for modification 15 February 2005/ Accepted 25 May 2005

SIT is a transmembrane adapter protein that modulates signals emanating from the T-cell receptor (TCR). Here, we have used gene-targeted mice to assess the role of SIT for T-cell development and peripheral T-cell functions. SIT^–/– double-positive thymocytes show an upregulation of the activation markers CD5 and CD69, suggesting that SIT negatively regulates TCR-mediated signals at the CD4⁺ CD8⁺ stage of thymic development. This assumption is further supported by the observation that in female H-Y TCR transgenic mice, positive selection is enhanced and even converted to negative selection. Similarly, mature peripheral T cells are hyperresponsive towards TCR-mediated stimuli and produce larger amounts of T-helper 1 (TH1) cytokines, and SIT-deficient mice show an increased susceptibility to develop experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. These results demonstrate that SIT is a critical negative regulator of TCR-mediated signaling and finely tunes the signals required for thymic selection and peripheral T-cell activation.

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