Abstracts (complete list) - Wissenschaft Online

Uwe Koelsch, Burkhart Schraven, Luca Simeoni
SIT and TRIM determine T-cell fate in the thymus
Thymic selection is a tightly regulated developmental process essential for establishing
central tolerance. Based upon experimental evidence, the intensity of TCR-mediated
signaling is a key factor for determining cell fate in the thymus. It is widely accepted
that low-intensity signals result in positive selection, whereas high-intensity signals turn
on the negative selection program. Transmembrane adaptor proteins (TRAPs) have
been demonstrated to be important regulators of T-cell activation. However, little is
known on their role during T-cell development. We have previously shown that the
transmembrane adaptor SIT regulates positive selection, whereas mice lacking the Tcell
receptor interacting molecule (TRIM) showed normal T-cell development. As SIT
and TRIM represent two related TRAPs strongly expressed in thymocytes, we have
explored the possibility that they may share redundant functions during thymocyte
selection. We found that SIT and TRIM cooperatively regulate TCR signaling potential,
thus in turn influencing the outcomes of selection. Indeed, loss of both SIT and TRIM
resulted in the upregulation of CD5, CD69 and TCRbeta expression, strong MAPK
activation and enhanced positive selection. Moreover, by crossing SIT/TRIM doubledeficient
mice onto transgenic mice carrying TCRs with different avidity/affinity, we
found profound alterations of T-cell development. Unexpectedly, loss of SIT and TRIM
resulted in a shift from non selection to positive selection whereas positive selection was
converted to negative selection. In summary, we have demonstrated that SIT and TRIM
have the striking ability to regulate cell fate of developing thymocytes, thus identifying
TRAPs as essential regulators of central tolerance.