NF-kappa B1 p105 regulates T cell homeostasis and prevents chronic inflammation.
Transcription factor NF-kappaB is regulated by a family of inhibitors, IkappaBs, as well as the NF-kappaB1 and NF-kappaB2 precursor proteins, p105 and p100. Although the different NF-kappaB inhibitors can all inhibit NF-kappaB in vitro, their physiological functions are incompletely understood. In this study, we demonstrate that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice lacking p105, but expressing the mature NF-kappaB1 p50, spontaneously develop intestinal inflammation with features of human inflammatory bowel disease. This inflammatory disorder occurs under specific pathogen-free conditions and critically involves T cells. Consistently, the p105-deficient mice have reduced frequency of naive T cells and increased frequency of memory/effector T cells in the peripheral lymphoid organs. Although p105 is dispensable for the production of immunosuppressive regulatory T cells, p105 deficiency renders CD4 T cells more resistant to Treg-mediated inhibition. We further show that the loss of p105 results in hyperproduction of Th17 subset of inflammatory T cells. Together, these findings suggest a critical role for NF-kappaB1 p105 in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation.
Chang
Mikyoung
M
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030, USA.
Lee
Andrew J
AJ
Fitzpatrick
Leo
L
Zhang
Minying
M
Sun
Shao-Cong
SC
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D018836:Inflammation Mediators; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse