Journal
CELL
Volume 180, Issue 1, Pages 79-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.11.026
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Categories
Funding
- NIH Shared Instrumentation [S10OD010584-01A1, S10OD018338-01]
- Cancer Center Support at the Laura and Isaac Perlmutter Cancer Center [NIH/NCI P30CA016087]
- HHMI Fellowship of the Damon Runyon Cancer Research Foundation [2232-15]
- Dale and Betty Frey Fellowship of the Damon Runyon Cancer Research Foundation [2105-12]
- Alberta Innovates Fellowship
- National Multiple Sclerosis Society [FG 2089-A-1]
- Howard Hughes Medical Institute
- Helen and Martin Kimmel Center for Biology and Medicine
- NIH [R01AI143861, R01AI121436, R01DK103358]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001255] Funding Source: NIH RePORTER
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Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by ROR gamma t-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4(+) T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.
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