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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4273-7282.
Prepublished online as a Blood First Edition Paper on February 6, 2008; DOI 10.1182/blood-2007-10-115667.

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IMMUNOBIOLOGY

Itch–/–{alpha}β and {gamma}{delta} T cells independently contribute to autoimmunity in Itchy mice

Valentino Parravicini1, Anne-Christine Field1, Peter D. Tomlinson1, M. Albert Basson2, and Rose Zamoyska1

1 Division of Molecular Immunology, Medical Research Council (MRC) National Institute for Medical Research, London; and 2 Department of Cranofacial Development, King's College London, London, United Kingdom

E3 ubiquitin ligases determine which intracellular proteins are targets of the ubiquitin conjugation pathway and thus play a key role in determining the half-life, subcellular localization and/or activation status of their target proteins. Itchy mice lack the E3 ligase, Itch, and show dysregulation of T lymphocytes and the induction of a lethal autoimmune inflammatory condition. Itch is widely expressed in hematopoietic and nonhematopoietic cells, and we demonstrate that disease is transferred exclusively by hematopoietic cells. Moreover, distinct manifestations of the autoimmune inflammatory phenotype are contributed by discrete populations of lymphocytes. The presence of Itch-deficient {alpha}β T cells drives expansion of peritoneal B1b cells and elevated IgM levels, which correlate with itching and pathology. In contrast, Itch–/– interleukin-4–producing {gamma}{delta} T cells, even in the absence of {alpha}β T cells, are associated with elevated levels of IgE and an inflammatory condition. These data indicate that disruption of an E3 ubiquitin ligase in {alpha}β T cells can subvert a B-cell subpopulation, which normally functions to control particular microbial pathogens in a T-independent manner, to contribute to autoimmunity. In addition, disruption of Itch in innate {gamma}{delta} T cells can influence autoimmune pathology and might therefore require distinct therapeutic intervention.


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