Conditional Deletion of Shp2 Tyrosine Phosphatase in Thymocytes Suppresses Both Pre-TCR and TCR Signals

Abstract

It is well known that T cell differentiation and maturation in the thymus is tightly controlled at multiple checkpoints. However, the molecular mechanism for the control of this developmental program is not fully understood. A number of protein tyrosine kinases, such as Zap-70, Lck, and Fyn, have been shown to promote signals required for thymocyte development, whereas a tyrosine phosphatase Src homology domain-containing tyrosine phosphatase (Shp)1 has a negative effect in pre-TCR and TCR signaling. We show in this study that Shp2, a close relative of Shp1, plays a positive role in T cell development and functions. Lck-Cre-mediated deletion of Shp2 in the thymus resulted in a significant block in thymocyte differentiation/proliferation instructed by the pre-TCR at the β selection step, and reduced expansion of CD4+ T cells. Furthermore, mature Shp2−/− T cells showed decreased TCR signaling in vitro. Mechanistically, Shp2 acts to promote TCR signaling through the ERK pathway, with impaired activation of ERK kinase observed in Shp2−/− T cells. Thus, our results provide physiological evidence that Shp2 is a common signal transducer for pre-TCR and TCR in promoting T cell maturation and proliferation.

SH2 Domain-Containing Phosphatase-2 Protein-Tyrosine Phosphatase Promotes FcεRI-Induced Activation of Fyn and Erk Pathways Leading to TNFα Release from Bone Marrow-Derived Mast Cells

“…Our findings point to a positive role for SHP2 in certain arms of the FcRI signaling cascade. Consistent with studies of SHP2 in other cell types and pathways (24,47), we find that SHP2 promotes activation of Jnk and Erk MAPKs, Akt and IKK pathways downstream of FcRI. This effect is consistent with elevated Lyn activity and reduced Fyn signaling in SHP2 KO BMMCs.…”

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

“…50), and B and T lymphocyte attenuator (BTLA; Ref 51). Because SHP-2 has been implicated in both inhibitory (52,53) and stimulatory (54,55) signaling cascades, its contribution to CEACAM1-dependent effects must still be defined.…”

A VISTA on PD-1H

“…One of the first clues to reconcile the antibody-specific differences was the demonstration by Wang et al that their anti-VISTA antibody shows almost undetectable levels of VISTA after T cell activation, while Flies et al observed substantial elevation of PD-1H on both CD4 + and CD8 + T cells after activation. These fickle antibodies highlight what students of immunology have learned from mice: it is not a good idea to discern biology of a molecule by its antibodies (7)(8)(9)(10). In this issue, Flies et al (11) elucidate the biological function of PD-1H using mice with targeted mutation of the gene encoding PD-1H.…”