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Title: Forward genetic analysis of natural T regulatory cell development
Author: Salisbury, Emma
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Natural (n) T regulatory (Treg) cells generated in the thymus are essential throughout life for the maintenance of T cell homeostasis and prevention of autoimmunity. T cell receptor (TCR)/CD28-mediated activation of Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NFB) and Jun N-terminal kinase (JNK) pathways is known to play a key role in nTreg development but many of the predicted molecular interactions are based on extrapolations from non-Treg cell TCR stimulation with non-physiological ligands. For the first time, this work provides strong genetic evidence of a scaffold function for the Caspase Recruitment Domain (CARD) of the TCR signalling protein CARD-MAGUK1 (CARMA1) in nTreg development in vivo. I report two, new, N-ethyl-N-nitrosourea (ENU)-derived mutant mice, Vulpo and Zerda, with a profound block in the development of nTregs in the thymus as well as impaired inducible (i) Treg differentiation in the periphery. Despite independent heritage, both mutants harbour different point mutations in the CARD of the CARMA1 protein. vulpo and zerda mutations do not affect expression levels of CARMA1 but still impair signalling through the TCR due to defective downstream B cell CLL/Lymphoma 10 (Bcl-10) protein recruitment by the mutated CARD of CARMA1. Phenotypic differences observed between Vulpo and Zerda mutants suggest a role for the CARD of CARMA1 independent of Bcl-10 activation of downstream pathways. I conclude that this forward genetic approach demonstrates a critical role for the CARD function of CARMA1 in Treg development in vivo.
Supervisor: Ashton-Rickardt, Philip ; Pusey, Charles Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral