Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal ...cbdm.hms. · PDF file Glut1 depletion leads to decreased B cell number and antibody production, glycolytic rewiring is

Article

Fasting-Refeeding Impacts Immune Cell Dynamics

and Mucosal Immune Responses

Graphical Abstract

Highlights

d Fasting drastically reduces lymphocyte levels in Payer’s

patches

d Naive B cells migrate to bonemarrow during fasting and then

back upon refeeding

d Nutritional signals are essential to maintain CXCL13

expression by stromal cells

d Fasting causes GC B cell death and attenuates antigen-

specific IgA response

Nagai et al., 2019, Cell 178, 1072–1087 August 22, 2019 ª 2019 Elsevier Inc. https://doi.org/10.1016/j.cell.2019.07.047

Authors

Motoyoshi Nagai, Ryotaro Noguchi,

Daisuke Takahashi, ..., Keiyo Takubo,

Taeko Dohi, Koji Hase

Correspondence [email protected]

In Brief

Temporary fasting drastically reduces the

levels of B cells in Peyer’s patches, with

germinal center B cells undergoing

apoptosis and naive cells migrating to the

bone marrow and only egressing upon

refeeding.

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Article

Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses Motoyoshi Nagai,1,2 Ryotaro Noguchi,1,2 Daisuke Takahashi,1 Takayuki Morikawa,3 Kouhei Koshida,1 Seiga Komiyama,1

Narumi Ishihara,1 Takahiro Yamada,1 Yuki I. Kawamura,2 Kisara Muroi,1 Kouya Hattori,1 Nobuhide Kobayashi,1

Yumiko Fujimura,1 Masato Hirota,1 Ryohtaroh Matsumoto,1 Ryo Aoki,4,5 Miwa Tamura-Nakano,6 Machiko Sugiyama,2,7

Tomoya Katakai,8 Shintaro Sato,9,10 Keiyo Takubo,3 Taeko Dohi,1,2 and Koji Hase1,10,11,* 1Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo 105-8512, Japan 2Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and

Medicine, Chiba 272-8516, Japan 3Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan 5Institute of Health Sciences, Ezaki Glico Co., Ltd., Osaka 555-8502, Japan 6Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan 7Laboratory for Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-045, Japan 8Department of Immunology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan 9Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka

University, Osaka 565-0871, Japan 10International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, the University of Tokyo (IMSUT),

Tokyo 108-8639, Japan 11Lead Contact

*Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.07.047

SUMMARY

Nutritional status potentially influences immune re- sponses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by �50% in Peyer’s patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induc- tion of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food anti- gen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.

INTRODUCTION

Inappropriate calorie intake is a global health problem. In devel-

oping countries, the nutritional deficiency often compromises

vaccination efficacy and increases the risk of infectious dis-

eases (Kaufman et al., 2011; Savy et al., 2009; Scrimshaw and

SanGiovanni, 1997). Furthermore, childhood malnutrition is a

predisposing factor for environmental enteropathy characterized

by intestinal dysfunction, increased intestinal permeability, and

microbial dysbiosis (Brown et al., 2015; Humphrey, 2009). In

industrialized countries, on the other hand, excessive food intake

accompanied by a lack of exercise has augmented the incidence

of obesity (World Health Organization, 2016), which is a signifi-

cant risk factor for cardiovascular disease, metabolic syn-

dromes, and cancer (Basen-Engquist and Chang, 2011; Grundy,

2004; Poirier et al., 2006). Low-grade inflammation due to

obesity is significantly implicated in the development of these

diseases (Visscher and Seidell, 2001). These observations

indicate that nutritional status has a significant impact on the

immune system.

The gastrointestinal mucosa is directly exposed to exogenous

food ingredients and thus inevitably faces drastic changes in the

nutritional status of the lumen during food uptake and fasting.

We previously demonstrated that intestinal tissue is highly sus-

ceptible to deprivation of luminal nutrients, as temporal fasting

arrested epithelial cell proliferation while refeeding induced hy-

perproliferation in the intestinal epithelium (Okada et al., 2013).

Given that epithelial cell turnover constitutes a robust first-line

barrier to external antigens, mucosal barrier function may be

more vulnerable during fasting than during feeding. Considering

that fasting relieves the burden of food-borne antigens and

microorganisms on the gut mucosa, it is thus reasonable to

decelerate epithelial cell turnover temporarily to minimize energy

expenditure under nutrient deprivation.

The gut mucosal barrier consists of not only intestinal epithe-

lium but also an underlying immune system that establishes the

second-line barrier. The gutmucosal immune response is charac-

terized by the production of dimeric or polymeric immunoglobulin

1072 Cell 178, 1072–1087, August 22, 2019 ª 2019 Elsevier Inc.

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A

B

C

D E

Figure 1. Characterization of PPs during Fasting and Refeeding

(A) Serial sections of PP were stained with H&E. PPs were obtained frommice fed ad libitum (left), fasted for 36 h (middle), or refed with CE2 for 48 h (right). Scale

bar, 200 mm.

(B) Immunostaining of PPs from mice fed ad libitum (left), mice fasted for 36 h (middle), and mice refed with CE2 for 48 h (right). Scale bar, 200 mm.

(legend continued on next page)

Cell 178, 1072–1087, August 22, 2019 1073

A (IgA) to the mucosal surface (Lycke and Bemark, 2017).

Secretory IgA (S-IgA) plays vital roles in host defense against

pathogens, inhibition of microbial metabolite penetration, and

regulation of the gut microbial community (Mantis et al., 2011;

Uchimura et al., 2018; Wei et al., 2011). To efficiently induce

S-IgA response, luminal antigens are actively taken to gut-associ-

ated lymphoid tissue, such as Peyer’s patches (PPs), that serve

as an inductive site of mucosal immunity. In PPs, germinal center

(GC) reactions, namely, class switch recombination to IgA as well

as affinity maturation, occur continuously with the aid of follicular

helper T (Tfh) cells. IgA class-switched B cells subsequently

egress PPs and then home to the intestinal lamina propria via

mesenteric lymph nodes (MLNs), the thoracic duct, and blood

circulation, during which IgA+ B cells terminally differentiate into

IgA-producing plasma cells.

Multiple lines of research have uncovered a link between im-

mune cell function and metabolic status (Kau et al., 2011; Man

and Kallies, 2015). For example, upon T cell receptor (TCR) stim-

ulation, effector T (Teff) cells enhance the uptake and utilization

of glucose to promote aerobic glycolysis. Activated Teff cells

also upregulate glutaminolysis. Such metabolic reprogramming

is essential for Teff cells to meet the energy demand of clonal

expansion and effector functions, such as the production of

inflammatory cytokines (Carr et al., 2010). Furthermore, IgA+

plasma cells in the intestine preferentially utilize glycolysis for en-

ergy metabolism, whereas naive B cells in PPs usually gain ATP

through aerobic metabolism in mitochondria (Kunisawa et al.,

2015). Stimulation with lipopolysaccharides (LPS) or B cell re-

ceptor (BCR) ligation upregulates glucose transporter 1 (Glut1)

expression in B cell activating factor (BAFF)-pretreated B cells,

which eventually undergo metabolic reprogramming to glycol-

ysis (Caro-Maldonado et al., 2014). Because B cell-specific