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Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

ABSTRACT: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

SUBMITTER: Kuehn HS

PROVIDER: S-EPMC4371526 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

Kuehn Hye Sun HS Ouyang Weiming W Lo Bernice B Deenick Elissa K EK Niemela Julie E JE Avery Danielle T DT Schickel Jean-Nicolas JN Tran Dat Q DQ Stoddard Jennifer J Zhang Yu Y Frucht David M DM Dumitriu Bogdan B Scheinberg Phillip P Folio Les R LR Frein Cathleen A CA Price Susan S Koh Christopher C Heller Theo T Seroogy Christine M CM Huttenlocher Anna A Rao V Koneti VK Su Helen C HC Kleiner David D Notarangelo Luigi D LD Rampertaap Yajesh Y Olivier Kenneth N KN McElwee Joshua J Hughes Jason J Pittaluga Stefania S Oliveira Joao B JB Meffre Eric E Fleisher Thomas A TA Holland Steven M SM Lenardo Michael J MJ Tangye Stuart G SG Uzel Gulbu G

Science (New York, N.Y.) 20140911 6204

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration o ...[more]

PMID: 25213377

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Project description:Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.

Dataset Information

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

Publications

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

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