Itch-/- alphabeta and gammadelta T cells independently contribute to autoimmunity in Itchy mice.
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 alphabeta T cells drives expansion of peritoneal B1b cells and elevated IgM levels, which correlate with itching and pathology. In contrast, Itch(-/-) interleukin-4-producing gammadelta T cells, even in the absence of alphabeta T cells, are associated with elevated levels of IgE and an inflammatory condition. These data indicate that disruption of an E3 ubiquitin ligase in alphabeta 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 gammadelta T cells can influence autoimmune pathology and might therefore require distinct therapeutic intervention.
Parravicini
Valentino
V
Division of Molecular Immunology, Medical Research Council, National Institute for Medical Research, London, UK.
Field
Anne-Christine
AC
Tomlinson
Peter D
PD
Basson
M Albert
MA
Zamoyska
Rose
R
D000818:Animals; D000906:Antibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D016026:Bone Marrow Transplantation; D016764:Cell Polarity; D049109:Cell Proliferation; D005122:Exudates and Transudates / Q000276:immunology; D006413:Hematopoietic System / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007075:Immunoglobulin M / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010537:Peritoneum / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*
D000906:Antibodies; D007075:Immunoglobulin M; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015847:Interleukin-4; D007073:Immunoglobulin E; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases