Dataset Information

Mast cells regulate CD4⁺ T-cell differentiation in the absence of antigen presentation.

ABSTRACT:

Background

Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD⁺) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown.

Objective

The objective of this study is to further dissect the mechanism of actions of NAD⁺ and determine the effect of APCs on NAD⁺-mediated T-cell activation.

Methods

Isolated dendritic cells and bone marrow-derived mast cells (MCs) were used to characterize the mechanisms of action of NAD⁺ on CD4⁺ T-cell fate in vitro. Furthermore, NAD⁺-mediated CD4⁺ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC^-/-, MHC class II^-/-, Wiskott-Aldrich syndrome protein (WASP)^-/-, 5C.C7 recombination-activating gene 2 (Rag2)^-/-, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD⁺ on the systemic immune response in the context of Listeria monocytogenes infection.

Results

Our in vivo and in vitro findings indicate that after NAD⁺ administration, MCs exclusively promote CD4⁺ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4⁺ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD⁺ resulted in decreased MHC II expression on CD11c⁺ cells, MC-mediated CD4⁺ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes.

Conclusions

Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD⁺ in the context of primary immunodeficiencies and antimicrobial resistance.

SUBMITTER: Rodriguez Cetina Biefer H

PROVIDER: S-EPMC6454881 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Mast cells regulate CD4<sup>+</sup> T-cell differentiation in the absence of antigen presentation.

Rodriguez Cetina Biefer Hector H Heinbokel Timm T Uehara Hirofumi H Camacho Virginia V Minami Koichiro K Nian Yeqi Y Koduru Suresh S El Fatimy Rachid R Ghiran Ionita I Trachtenberg Alexander J AJ de la Fuente Miguel A MA Azuma Haruhito H Akbari Omid O Tullius Stefan G SG Vasudevan Anju A Elkhal Abdallah A

The Journal of allergy and clinical immunology 20180220 6

<h4>Background</h4>Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown.<h4>Objective</h4>The objective of this study is to further dissect the mechanism of acti ...[more]

PMID: 29470999

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Project description:BackgroundAutoimmune hepatitis (AIH) is a T-cell-mediated autoimmune liver disease that can lead to liver injury and has a poor long-term prognosis. Mesenchymal stromal cells (MSCs) have immunosuppressive effects and can treat AIH. CD4+ T cells express the unique inhibitory Fcγ receptor (FcγRIIB), which is the only receptor for the immunosuppressive factor soluble fibrinogen-like protein 2 (sFgl2). This study aimed to examine the therapeutic effect of sFgl2 gene-modified MSCs (sFgl2-MSCs) on AIH.MethodsMSCs were obtained from the inguinal fat of mice and cocultured with CD4+ T cells sorted from mouse spleens. FcγRIIB expression on CD4+ T cells was determined by flow cytometry. sFgl2 expression in MSCs transfected with lentiviral vectors carrying the Fgl2 gene and a green fluorescent protein-encoding sequence was determined by enzyme-linked immunosorbent assay. The percentages of Th1 cells Th17 cells and regulatory T cells (Tregs) were determined by flow cytometry And the levels of p-SHP2 and p-SMAD2/3 were detected by Western blotting after the cells were cocultured with MSCs for 72 h. After locating MSCs by in vivo imaging Con A-induced experimental AIH mice were randomly divided into 4 groups and administered different treatments. After 24 h histopathological scores liver function and cytokine levels were examined and the proportions of CD4+ T cells CD8+ T cells Tregs Th17 cells and Th1 cells in the spleen and liver were determined by flow cytometry. In addition immunohistochemical staining was used to detect the liver infiltration of T-bet-, Foxp3- and RORγ-positive cells.ResultsFcγRIIB expression on CD4+ T cells was upregulated after coculture with MSCs. After coculture with sFgl2-MSCs, the proportion of Tregs among CD4+ T cells increased, the proportion of Th17 and Th1 cells decreased, and the levels of p-SHP2 and p-SMAD2/3 increased. In vivo, sFgl2-MSCs significantly improved liver function, decreased liver necrosis area, decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 expression, increased IL-10 expression, reduced liver infiltration of CD4+ T and CD8+ T cells, increased the proportion of Tregs and reduced the proportions of Th17 and Th1 cells in mice.ConclusionBy promoting Tregs differentiation and inhibiting Th17 and Th1 cell differentiation, sFgl2 gene-modified MSCs have a more powerful therapeutic effect on Con A-induced experimental AIH and may represent a strategy for the clinical treatment of AIH.

Dataset Information

Mast cells regulate CD4⁺ T-cell differentiation in the absence of antigen presentation.

Background

Objective

Methods

Results

Conclusions

Publications

Mast cells regulate CD4<sup>+</sup> T-cell differentiation in the absence of antigen presentation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation.

Background

Objective

Methods

Results

Conclusions

Publications

Mast cells regulate CD4<sup>+</sup> T-cell differentiation in the absence of antigen presentation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mast cells regulate CD4⁺ T-cell differentiation in the absence of antigen presentation.