Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells

Shb knockout mice did not display any major changes in thymocyte development despite an aberrant TCR signaling pattern, including increased basal activation and reduced stimulation-induced phosphorylation. The loss of Shb expression did however affect peripheral CD4+ TH cells resulting in an increased proliferative response to TCR stimulation and an elevated IL-4 production of na？ve TH cells. This suggests a TH2 skewing of the Shb knockout immune system, seemingly caused by an altered TCR signaling pattern.Our results indicate that Shb appears to play an important modulating role on TCR signaling, thus regulating the peripheral CD4+ TH2 cell response.The primary aim of T cell development is to create a fully competent T lymphocyte population in the periphery, capable of quickly identifying pathogens yet non-responsive to self-tissue [1,2]. To maintain this delicate balance, the immature thymocytes are subjected to rigorous control, where signaling through the T cell receptor (TCR) is of utmost importance [3-5]. Mature, peripheral T cells are equally dependent on the TCR, as activation and effector cell development are decided by TCR signaling strength and duration [6-8].Upon receptor engagement, a host of adaptor and effector proteins assemble at numerous phosphotyrosines within the cytoplasmic segment of the TCR signaling complex. Among the key players in this signaling system are the adaptors SLP76 [9,10] and linker for activation of T cells (LAT) [11,12], their association with the activated TCR and their subsequent phosphorylation that activates signaling through phospholipase C-γ (PLC-γ) [13], as well as Ras and the Rho family of GTPases [14,15], which in turn enable activation of more distal pathways such as the various variants of mitogen activated kinases (MAPKs) [16-18]. Loss of early signaling elements, such as LAT or SLP76 therefore has profound effects on T cell development and function, with an almost complete block at the very first thymocyte developme