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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

Biefer, Hector Rodriguez Cetina^1,2,4  Heinbokel, Timm^1,2,5  Uehara, Hirofumi⁶  Camacho, Virginia⁷  Minami, Koichiro^1,2  Nian, Yeqi^1,2  Koduru, Suresh⁸  El Fatimy, Rachid³  Ghiran, Ionita⁹  Trachtenberg, Alexander J.¹⁰  de la Fuente, Miguel A.¹¹  Azuma, Haruhito⁶  Akbari, Omid¹²  Tullius, Stefan G.^1,2  Vasudevan, Anju¹³  Elkhal, Abdallah^1,2 

[1] Harvard Med Sch, Brigham & Womens Hosp, Div Transplant Surg, Boston, MA USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Transplantat Surg Res Lab, Boston, MA USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Initiat RNA Med, Dept Neurol,Ctr Neurol Dis, Boston, MA USA

[4] Univ Hosp Zurich, Clin Cardiovasc Surg, Zurich, Switzerland

[5] Charite Univ Med Berlin, Dept Nephrol, Berlin, Germany

[6] Osaka Med Coll, Dept Urol, Takatsuki, Osaka, Japan

[7] Harvard Stem Cell Inst, Beth Israel Deaconess Med Ctr, Flow Cytometry Core Facil, Boston, MA USA

[8] Harvard Stem Cell Inst, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA

[9] Univ Hyderabad, Sch Med Sci, Hyderabad, Telangana, India

[10] StART Families, Boston, MA USA

[11] Univ Valladolid, Inst Biol & Genet Mol, Valladolid, Spain

[12] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol, Los Angeles, CA USA

[13] Harvard Med Sch, McLean Hosp, Div Basic Neurosci, Angiogenesis & Brain Dev Lab, Belmont, MA USA

关键词: Nicotinamide adenine dinucleotide;    mast cells;    T cells;    antigen presentation;    MHC;    T-cell receptor;    CD4(+) T-cell differentiation;    dendritic cells;    macrophages;    Listeria monocytogenes;    cytokine;   

DOI  :  10.1016/j.jaci.2018.01.038

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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