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


Rodriguez Cetina Biefer, Hector; Heinbokel, Timm; Uehara, Hirofumi; Camacho, Virginia; Minami, Koichiro; Nian, Yeqi; Koduru, Suresh; El Fatimy, Rachid; Ghiran, Ionita; Trachtenberg, Alexander J; de la Fuente, Miguel A; Azuma, Haruhito; Akbari, Omid; Tullius, Stefan G; Vasudevan, Anju; Elkhal, Abdallah (2018). Mast cells regulate CD4 T-cell differentiation in the absence of antigen presentation. Journal of Allergy and Clinical Immunology, 142(6):1894-1908.e7.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Vascular Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Uncontrolled Keywords:CD4(+) T-cell Differentiation Listeria monocytogenes MHC Nicotinamide adenine dinucleotide T cells T-cell receptor antigen presentation cytokine; dendritic cells macrophages mast cells
Language:English
Date:December 2018
Deposited On:22 Feb 2019 13:40
Last Modified:29 Jul 2020 09:40
Publisher:Elsevier
ISSN:0091-6749
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jaci.2018.01.038
PubMed ID:29470999

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