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Elife. 2016 Mar 21;5. pii: e08384. doi: 10.7554/eLife.08384.

Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions.

Author information

1
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
2
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.

Abstract

The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4(+) 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology.

KEYWORDS:

STAT signaling; STAT5; T cells; autoimmunity; cell biology; cytokine; immunology; mouse; transcription factors

PMID:
26999798
PMCID:
PMC4856466
DOI:
10.7554/eLife.08384
[Indexed for MEDLINE]
Free PMC Article

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