Increased gc receptor expression does not augment but paradoxically inhibits gc cytokine signaling and ameliorates lethal autoinflammatory disease

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NCI	IMMUNO-14

* FARE Award Winner

Authors

• J. Park
• A.T. Waickman
• C. Hong
• H. Park

Abstract

The common gamma cytokine receptor (gc) is the shared signaling unit for common gamma cytokines and its expression is essential for lymphocyte development and T cell activation. The current paradigm in cytokine signaling posits that increased cytokine receptor expression would result in increased cytokine signaling. However, we found it was the opposite for gc as gc transgenic (gcTg) T cells, expressing increased levels of gc, were profoundly impaired in gc cytokine signaling as demonstrated by significantly decreased STAT5 and Akt phosphorylation upon IL-7 signaling. Mechanistically, we found that the gc-associated receptor tyrosine kinase JAK3 was expressed in limited amounts in T cells so that increased gc expression presumably results in the appearance of gc that fails to recruit JAK3. To assess the effect in vivo, we introduced the gcTg into scurfy mice, which is a model of lethal autoinflammation with deficiency of Foxp3 expression required for CD4+ regulatory T cell generation. Strikingly, gc overexpression in scurfy mice significantly improved the disease outcome and dampened inflammation with prolonged survival. Collectively, these results document a critical role for gc signaling in inflammation and report a new mechanism of regulating gc signaling that is suppressed by increased expression of gc.

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