Conditional deletion of Shp2 tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCR signals

TV Nguyen, Y Ke, EE Zhang, GS Feng - The Journal of Immunology, 2006 - journals.aai.org
The Journal of Immunology, 2006journals.aai.org
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 …
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.
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