The tumor suppressor CYLD controls the function of murine regulatory T cells.
CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. We have previously described a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8)). In this study, we demonstrate that CYLD plays a critical role in Treg development and function. T cells of CYLD(ex7/8) mice had a hyperactive phenotype manifested by increased production of inflammatory cytokines and constitutive activation of the NF-κB pathway. Furthermore, the amount of Foxp3(+) regulatory T cells in these mice was markedly enhanced in thymus and peripheral organs. Importantly, these regulatory T cells displayed decreased expression levels of CD25 and CTLA-4 associated with impaired suppressive capacity. Hence, our data emphasize an essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses.
Institute for Molecular Medicine, Johannes Gutenberg-University of Mainz, 55131 Mainz, Germany.
Sonja
S
Reissig
Nadine
N
Hövelmeyer
Benno
B
Weigmann
Alexei
A
Nikolaev
Bettina
B
Kalt
Thomas F
TF
Wunderlich
Matthias
M
Hahn
Marcus F
MF
Neurath
Ari
A
Waisman
D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D060908:CTLA-4 Antigen; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases