title: SHARPIN controls the development of regulatory T cells.
abstract: SHARPIN is an essential component of the linear ubiquitin chain assembly complex (LUBAC) complex that controls signalling pathways of various receptors, including the tumour necrosis factor receptor (TNFR), Toll-like receptor (TLR) and antigen receptor, in part by synthesis of linear, non-degrading ubiquitin chains. Consistent with SHARPIN's function in different receptor pathways, the phenotype of SHARPIN-deficient mice is complex, including the development of inflammatory systemic and skin diseases, the latter of which depend on TNFR signal transduction. Given the established function of SHARPIN in primary and malignant B cells, we hypothesized that SHARPIN might also regulate T-cell receptor (TCR) signalling and thereby control T-cell biology. Here, we focus primarily on the role of SHARPIN in T cells, specifically regulatory T (Treg) cells. We found that SHARPIN-deficient (Sharpin(cpdm/cpdm) ) mice have significantly reduced numbers of FOXP3(+) Treg cells in lymphoid organs and the peripheral blood. Competitive reconstitution of irradiated mice with mixed bone marrow from wild-type and SHARPIN-deficient mice revealed an overall reduced thymus population with SHARPIN-deficient cells with almost complete loss of thymic Treg development. Consistent with this cell-intrinsic function of SHARPIN in Treg development, TCR stimulation of SHARPIN-deficient thymocytes revealed reduced activation of nuclear factor-κB and c-Jun N-terminal kinase, establishing a function of SHARPIN in TCR signalling, which may explain the defective Treg development. In turn, in vitro generation and suppressive activity of mature SHARPIN-deficient Treg cells were comparable to wild-type cells, suggesting that maturation, but not function, of SHARPIN-deficient Treg cells is impaired. Taken together, these findings show that SHARPIN controls TCR signalling and is required for efficient generation of Treg cells in vivo, whereas the inhibitory function of mature Treg cells appears to be independent of SHARPIN.
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Redecke
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Chaturvedi
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jeeba
authors.initials: J
authors.lastname: Kuriakose
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Häcker
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D060168:Thymocytes / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C425287:sharpin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: LUBAC; SHARPIN; T-cell development; regulatory T cells; signal transduction