T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function

TY - JOUR

T1 - T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function

AU - Garrido-Mesa, N.

AU - Schroeder, J-H.

AU - Stolarczyk, E.

AU - Gallagher, A. L.

AU - Lo, J. W.

AU - Bailey, C.

AU - Campbell, L.

AU - Sexl, V.

AU - Macdonald, T. T.

AU - Howard, J. K.

AU - Grencis, R. K.

AU - Powell, N.

AU - Lord, G. M.

PY - 2019/1

Y1 - 2019/1

N2 - Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system, microbiota dependent colitis occurs due to aberrant ILC3 responses, thus T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic versus protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.

AB - Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system, microbiota dependent colitis occurs due to aberrant ILC3 responses, thus T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic versus protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.

UR - http://www.scopus.com/inward/record.url?scp=85055560183&partnerID=8YFLogxK

U2 - 10.1038/s41385-018-0092-6

DO - 10.1038/s41385-018-0092-6

M3 - Article

SN - 1933-0219

VL - 12

SP - 51

EP - 63

JO - Mucosal Immunology

JF - Mucosal Immunology

IS - 1

ER -