ABSTRACT
Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
Subject(s)
STAT3 Transcription Factor/metabolism , T-Lymphocytes/cytology , Cell Separation , Cytokines/metabolism , Flow Cytometry , Humans , Interferon-gamma/metabolism , Interleukin-17/metabolism , Interleukin-23/metabolism , Interleukins/metabolism , Killer Cells, Natural/cytology , Leukocytes, Mononuclear/cytology , Lymphocytes/cytology , Mutation , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Polymorphism, Single Nucleotide , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Interleukin/metabolism , Receptors, Interleukin-12/metabolism , Receptors, Interleukin-21/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The relationship between dietary intake and systemic availability of retinol is likely to be complex because although retinol is an essential nutrient, it is toxic at high levels. The present study determined whether rates of transapical retinol absorption are modulated so that availability is increased at low dietary levels, but decreased when dietary intake is excessive. Juvenile hybrid striped bass were fed for 6 wk diets with 568 (below), 1657 (approximating the requirement) and 40,244 (excessive) micro g/kg dry diet of trans retinol. Proximal small intestine segments were used to measure rates of retinol absorption and tissue concentrations. Initial and final body mass did not differ among groups; deficiency and toxicity symptoms were not observed. Uptake of tracer retinol was inhibited by unlabeled retinol, indicating the presence of saturable, carrier-mediated absorption. Increasing dietary levels of retinol increased the rates of absorption measured at 0.05 mmol/L [8.04 +/- 0.65; 15.2 +/- 1.53; 25.1 +/- 3.4 pmol/(mg. min) for below, approximating and exceeding the retinol requirement; P < 0.0001]; this resulted in higher tissue concentrations of all-trans retinol (0.21 +/- 0.03, 0.49 +/- 0.21 and 338 +/- 89 pmol/g; P < 0.0001) and dehydro-retinol (0.11 +/- 0.04, 0.91 +/- 0.04, and 454 +/- 109 pmol/g; P < 0.001). These findings suggest that the systemic availability of various dietary levels of retinol is modulated after transapical absorption.
