Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 7, Pages 1419-1431Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122239
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Funding
- National Institutes of Health [R37 CA49152, R01 CA 114945]
- Terry Fox Program Project
- CIHR
- Ontario Ministry of Health and Long Term Care
- Princess Margaret Cancer Foundation
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The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell-intrinsic role of Shp1, we characterized mice with a T cell-specific Shp1 deletion (Shp1(fl/fl) CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1(fl/fl) CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4(+) T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1-deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44(hi) population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes.
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