obesity predisposes to th17 bias

Obesity predisposes to Th17 bias

Shawn Winer�1, Geoff Paltser�1, Yin Chan1, Hubert Tsui1,

Edgar Engleman2, Daniel Winer2 and H.-Michael Dosch1

1 Neuroscience and Mental Health program, Research Institute, The Hospital for Sick Children,

University of Toronto Departments of Pediatrics & Immunology, Toronto, Ontario Canada2 Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA

Obesity is associated with numerous inflammatory conditions including atherosclerosis,

autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity-

associated rises in TNF-a, IL-6 and TGF-b are believed to contribute. Here we demonstrate that

obesity selectively promotes an expansion of the Th17 T-cell sublineage, a subset with

prominent pro-inflammatory roles. T-cells from diet-induced obese mice expand Th17 cell

pools and produce progressively more IL-17 than lean littermates in an IL-6-dependent

process. The increased Th17 bias was associated with more pronounced autoimmune

disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In

both, diet-induced obese mice developed more severe early disease and histopathology with

increased IL-171 T-cell pools in target tissues. The well-described association of obesity with

inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

Key words: Autoimmunity . IL-17 . Obesity

Supporting Information available online

Introduction

Epidemiological evidence has linked obesity to pro-inflammatory

conditions such as cancer, asthma and autoimmune diseases

[1, 2]. The link with cancer is particularly strong, with obesity

emerging as a premier risk factor. Obesity predisposes to several

(but not all) autoimmune disorders, including inflammatory

bowel disease (IBD) and psoriasis [3, 4]. The Th17 T-cell

sublineage plays core roles in IBD and psoriasis, and recent

evidence demonstrates a pathogenic role for the Th17 inducer,

IL-23, in solid tumor animal models [5].

Diet-induced obese (DIO) mice and obese humans have

elevated serum and tissue levels of IL-6 [6, 7]. Adipocytes and

tissue-derived macrophages both contribute significantly to IL-6

expression, estimated at �33 and �20%, respectively [8]. IL-6

signaling through STAT-3, along with retinoic orphan receptor

a- and gt transcription factors, promote Th17 lineage expansion,

establishing an inter-organ system communication [9]. We

further explored the functional sequelae of the potential

connection between obesity and Th17 expansion.

Results and discussion

Obesity promotes IL-6-dependent Th17 sublineagebias

We first compared the proportions of CD41 Th17 cells in non-

immunized spleen cells from DIO and regular diet (RD) mice

(Fig. 1A, Supporting Information Fig. 1A). There were approximately

3� more IL-17 secreting CD41 systemic T cells in DIO mice

compared with age-matched, naive mice on RD. This expansion was

Th17 sublineage selective, for example, DIO neither affects systemic

pool sizes of CD41, IFN-g1(Th1), nor Foxp31regulatory T cells

SHORT COMMUNICATION

�These authors contributed equally to this work.Correspondence: Professor H.-Michael Dosche-mail: [email protected]

& 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

Eur. J. Immunol. 2009. 39: 2629–2635 DOI 10.1002/eji.200838893 Clinical immunology 2629

(Treg) (Fig. 1B, Supporting Information Fig. 1B and C), and GATA31

Th2 cell pools were not affected by obesity (Supporting Information

Fig. 2A). The enlarged Th17 pools in DIO mice were functional, with

enhanced IL-17 production after in vitro stimulation with anti-CD3

plus anti-CD28, while IFN-g (Fig. 1C) and Th2 cytokine secretion

(Supporting Information Fig. 2B) were similar in cultures of DIO and

RD splenocytes.

DIO thus generates an immunological phenotype with selec-

tive expansion of the Th17 sublineage. As is well established

[9, 10], frequencies of Th17 cells were small and we therefore

determined whether this Th17 sublineage bias is maintained

during active T-cell priming and expansion. We measured Th17

and Th1 cell populations in draining lymph nodes following

immunization of DIO and RD mice with a well-characterized

H-2b-binding peptide, myelin oligodendrocyte glycoprotein

35–55 (MOG35-55) [11]. Six days after immunization, lympho-

cytes from draining lymph nodes of DIO donors generated a

dramatically increased pool size of CD41 IL-171 cells, compared

with lymph node cells from RD mice (Fig. 1D). In contrast, the

CD41 IFN-g1 T cell compartment was unaffected by DIO.

Th17 development can proceed through both IL-6-dependent

and IL-6-independent pathways, the latter driven by IL-21 and

Figure 1. Obesity is associated with increased IL-17 bias. (A) Percentage of CD41IL-171 (upper panel) from total spleen cells of 16 wk-old B6 micefed a regular fat diet (white bars) or high fat diet (black bars) for 10 wk (n 5 9/group). Representative FACS plots from the above data are shown inthe lower panel. (B) Percentage of CD41IFN-g1 (upper panel) or CD41Foxp31 (lower panel) from total spleen cells of 16 wk-old B6 mice fed a regularfat diet (white bars) or high fat diet (black bars) for 10 wk (n 5 6/group). (C) Purified splenic CD41 T cells from obese or lean, 16 wk-old B6 mice werestimulated with aCD31aCD28 for 72 h. Proliferation (left panel), IL-17 secretion (middle panel) and IFN-g production (right panel) (n 5 4/group).(D) 16 wk-old WT and IL-6�/� B6 mice fed RD or high fat diet (DIO) were immunized with 100mg of MOG35-55 s.c. and the percentage ofCD41IL-171 (top panel) or CD41IFN-g1 (bottom panel) T cells in draining lymph nodes was determined 6 days after immunization (n 5 5/group).FACS plots show representative data from three to four independent experiments, with data pooled in the corresponding bar graphs; ��po0.01.

Eur. J. Immunol. 2009. 39: 2629–2635Shawn Winer et al.2630


TGF-b [12, 13]. We placed IL-6null mice on high fat diet and

immunized with MOG35-55 as above (Fig. 1D). Although DIO

IL-6null mice gained weight at similar rates as DIO WT mice

(Supporting Information Fig. 3), DIO IL-6null mice did not at all

develop the Th17 bias of DIO WT mice. These results indicate that

obesity-induced Th17 bias utilizes the IL-6-dependent pathway of

Th17 development.

DIO predisposes mice to severe, chronic trinitro-benzene sulfonic acid colitis

We analyzed the clinical impact of DIO in two Th17-dependent

disease models, trinitrobenzene sulfonic acid (TNBS) colitis and

EAE [10]. Depending on the mouse facility (e.g. gut flora),

C57BL/6 (B6) mice are fairly resistant [14] to TNBS colitis and

many animals recover within a week after disease induction. In

contrast, DIO rendered B6 mice highly susceptible to TNBS colitis

(Fig. 2). TNBS treated, DIO but not RD mice, demonstrated

progressive weight loss throughout the observation period

(Fig. 2A, B). DIO significantly accelerated the early disease stage,

with 50% lethality in the first week (Fig. 2C, po0.03, Life table),

although lethality in RD and DIO mice was ultimately similar.

Weight loss continued only in surviving DIO animals, due to more

severe colitis, both macroscopically (Fig. 2D) and histologically

(Fig. 2E, F) 10 days after disease induction. DIO colons showed

obvious thickening, fibrosis and shortening compared with RD

mice, with enhanced ulceration, loss of mucosal surface and

extensive transmural colon inflammation (Fig. 2D, F). Consistent

with increased DIO disease severity, isolated T cells from spleen,

draining mesenteric lymph nodes and lamina propria (LP) of

TNBS colitis DIO mice all produced significantly more IL-17 than

the corresponding T cells of RD mice (Fig. 2G).

DIO exacerbates EAE

Obesity-dependent Th17 expansion was thus associated with

progressively enhanced inflammatory and autoimmune tissue

lesions. To test the generality of this conclusion, we compared

EAE in DIO and RD mice. Lean and obese B6 mice, immunized

with MOG35-55 peptide, both showed first clinical symptoms 10

days later (Fig. 3A), DIO mice more rapidly progressed to severe

disease, with about half-reaching disease scores of 43 by day 13,

which took 20 days in RD mice (Fig. 3B). DIO worsened spinal

cord inflammation with more pronounced inflammatory cell

penetration in DIO white matter (Fig. 3C and D). T-cell recall

responses to MOG35-55 in EAE mice did not differ between DIO

and RD mice, suggesting that immunization was equally effective

(Fig. 3E). However, as in the TNBS model, T cells from DIO mice,

selectively and significantly, had higher IL-17 production than RD

mice in spleen, draining lymph nodes as well as the CNS target

tissue (Fig. 3F).

As the incidence of obesity increases worldwide, so will its

complications and associated disorders. There is an established

link between obesity and autoimmune/pro-inflammatory

diseases including psoriasis, IBD and asthma, all containing a

significant Th17 component [3, 4, 15, 16]. There is scant infor-

mation on a conceivable linkage between obesity and multiple

sclerosis, but one study showed reduced disease deterioration in

patients on low fat compared with high fat diet [17]. Although

EAE is not an ideal model for MS, data presented here suggest

that this association is worth investigating, in particular, since a

role for Th17 effectors in the penetration of the blood–brain

barrier as well as neuronal pathology has been reported [18].

In addition to autoimmune diseases, obesity has been asso-

ciated with risk to develop neoplastic disorders [2]. Recently, it

was shown that IL-23 and its downstream Th17 effector cells may

promote cancer through inhibition of anti-tumor CD81 T cells

and through enhanced production of tumor promoting MMP9

and angio-neogenesis [5, 19].

Th17 development requires critical signals that lead to

increased intracellular levels of STAT3. Although several cytokines

can promote Th17 expansion [10], we here demonstrate that

obesity-associated Th17 expansion is IL-6 dependent. Other cyto-

kines may further amplify this role of IL-6, indeed, serum amyloid

A, an acute-phase protein highly elevated in obesity, has been

shown to increase dendritic cell IL-23 production in vitro [20].

Concluding remarks

Collectively, our observations demonstrate that DIO predisposes to

IL-6-dependent Th17 expansion. DIO appeared not to accelerate

initiation, but rather exacerbate early disease progression. The

high prevalence of obese patients with spontaneous pro-inflam-

matory disorders may indicate an additional role of the Th17 axis

in disease initiation, not apparent in our experimentally induced

disease models. Future experiments will determine whether the

increase of Th17 effector cell frequency in DIO mice causes

autoimmune exacerbation directly or through involvement of

other effector cells/mechanisms that might identify new therapeu-

tic targets. DIO is reversible and it should be interesting to assess,

to what extent and at which disease stage weight loss can reduce

Th17 expansion and disease exacerbation, information that might

have clinical impact. While this present manuscript was in

submission, first observations from a small clinical study demon-

strated elevated IL-17 serum levels in obese patients [21],

suggesting that our observations in rodents are likely relevant to

human disease. IL-6-dependent Th17 expansion is a clinically

prominent element of pro-inflammatory diseases in obesity.

Materials and methods

Mice

All experiments were performed in male C57BL/6J (B6)

mice. WT animals were purchased from Jackson Laboratories

Eur. J. Immunol. 2009. 39: 2629–2635 Clinical immunology 2631


(Bar Harbor, ME, USA) (http://www.jax.org/) and maintained in

our vivarium in a pathogen-free, temperature controlled, 12 h

light and dark cycle environment. Animals were fed either

a RD or a high fat (60 kcal% fat) diet (Research Diets, New

Brunswick, NJ, USA). DIO mice received RD for the first

6 wk of life and then high fat diet for the following 10 wk. In

EAE and TNBS colitis experiments, 16 wk-old DIO mice

were maintained on high fat diet throughout the ex-

periments. All studies reported here used males under

approved protocols and in agreement with animal ethics guide-

lines.

Induction of EAE and TNBS colitis

EAE was induced in 16 wk-old male B6 mice. Briefly, mice were

immunized in each flank with 100mg of MOG35-55 (Alpha

diagnostic, San Antonio, TX, USA) emulsified in CFA (1:1)

Figure 2. DIO exacerbates chronic TNBS colitis. (A) Mean body weights (g) of living animals, (B) change (%) of body weight in animals surviving at agiven time point and (C) Life table analysis of 16 wk-old DIO and RD mice following intra-rectal TNBS (n 5 8/group). (D) Representative colons fromRD and DIO mice 10 days after TNBS administration (note the poorly formed stools, increased fibrosis and shortening of the DIO colon comparedwith RD mice. (E) Histological scoring (see Materials and methods). (F) Representative H&E-stained sections of colons from DIO and RD mice 10 daysafter TNBS administration (note the ulceration of the mucosal surface and transmural inflammation in the colons of DIO mice. (G) Secretion of IL-17(left panel) and IFN-g (right panel) 72 h after stimulation with aCD31aCD28. T cells were isolated from spleen (spln), draining mesenteric lymphnodes (LN) and LP 10 days after colitis induction (n 5 3/group). Unstimulated cytokine levels were below detection threshold, �po0.05, ��po0.01.



(Sigma-Aldrich, Oakville, ON, USA). In total 200 ng of pertussis

toxin (Sigma-Aldrich) was given i.p. on the day of EAE induction

and 48 h later. Animals were followed for at least 25 days and

disease was scored using the following scale: 0, asymptomatic; 1,

limp tail; 2, abnormal righting reflex and/or hind limb weakness;

3, unilateral hind limb paralysis; 4, bilateral hind limb paralysis

and 5, moribund or death.

TNBS colitis was induced in 16 wk-old B6 males. A final

concentration of 2.5% TNBS (Sigma-Aldrich, 50% ethanol) was

administered per rectum, using a 4F catheter. The catheter tip

was inserted 4 cm and 150mL of TNBS was injected slowly into

the colon while pulling out the catheter. The mouse was held in

the vertical position (30 s) after TNBS administration. Animals

were weighed daily over the next 10 days.

Histological analysis of the colon and CNS

Spinal cords and brains were removed 25 days after EAE

induction, and colons were removed 10 days after TNBS

administration. Both were fixed (24 h, 10% buffered formalin),

and then stained with H&E. Histology was scored by two blinded

observers and the average score was used. The following scoring

system for spinal cord histology was employed: 0, unremarkable;

1, focal mononuclear infiltration; 2, mononuclear infiltration

ino10% of white matter; 3, mononuclear infiltration in 10–20%

of white matter and 4, infiltration in 420% white matter.

For colon histology, the following scoring system was used:

0, no evidence of inflammation; 1, lymphocyte infiltrationo10%

of high power field (hpf) with no structural changes; 2, lympho-

cytic infiltration 10–25% of hpf and minor structural changes

including crypt elongation, mucosal thickening but no ulceration;

3, lymphocyte infiltration in 25–50% of hpf with bowel thickening

extending beyond the mucosal surface; and 4, lymphocyte infil-

tration in 450% of hpf with major structural changes including

crypt distortion, transmural bowel wall thickening and ulceration.

Isolation of splenic, LP and CNS mononuclear cells

Spleen cells were isolated as described [22]. CNS and LP

mononuclear cells were isolated 25 days after EAE or 10 days

Figure 3. DIO exacerbates MOG35-55-induced EAE. (A) Daily clinical EAE scores (methods) induced by MOG35-55 peptide in 16 wk-old DIO (n 5 14)and RD B6 mice (n 5 13). (B) Proportion of DIO and RD mice from the same experiment (A) with severe (4grade 3) EAE. (C) Blindly scored histologicalspinal cord sections (n 5 91) and (D) representative histological cord sections of mice with grade 31EAE, 25 days post disease induction. Arrows:lymphocytic infiltration in white matter. (E) In vitro MOG35-55-induced T-cell proliferation, (F) MOG35-55-induced (10 mg/mL) IL-17 (left panel) andIFN-g (right panel) secretion by purified lymphocytes from draining lymph nodes (LN), spleen and CNS, n 5 4 mice with grade 31EAE/group, 25 dayspost disease induction; unstimulated cytokine levels were below detection threshold, �po0.05, ]po0.0001.



after colitis induction. Brains and spinal cords were removed and

minced in a Stomacher blender. The suspension was then

incubated with 1 mg/mL collagenase (Sigma-Aldrich, 1 h/371C)

with gentle resuspension every 5 min. The suspensions were then

pelleted and suspended in 4 mL Percoll (Sigma-Aldrich, 30%) and

centrifuged at 1500 rpm/15 min over 4 mL 70% Percoll. The

mononuclear cells at the 30/70% Percoll interface were collected

and washed 2� in serum-free HL-1 medium, supplemented with

2 mM L-glutamine (Lonza, Walkersville, MD, USA).

LP cells: colons were removed and washed in calcium- and

magnesium-free HBSS (Gibco, Burlington, ON, USA) and cut into

small pieceso0.5 cm and incubated twice (20 min/371C) in HBSS,

2 mM DTT, 1 mM EDTA (Sigma-Aldrich), with manual shaking

every 5 min. The remaining tissue was then digested with 400 U/

mL collagenase in complete media (1 h/371C), with manual

shaking every 5 min. LP mononuclear cells were purified by

centrifugation through a discontinuous Percoll gradient of 40/

70%, washed 2� in serum-free HL-1 medium, supplemented

with 2 mM L-glutamine1antibiotics.

T-cell proliferation and cytokine secretion

In all EAE experiments, proliferation or cytokines were measured

following 72 h of stimulation with 10 mg/mL MOG35-55. In TNBS

colitis experiments, cytokines were measured following 72 h of

incubation with plate bound aCD3 (1mg/mL) and aCD28

(0.25 mg/mL). Splenocytes (4� 105/well) were incubated

(72 h/371C) in 96-well plates pre-coated with aCD3 (1 mg/mL)

and aCD28 (0.25 mg/mL) or varying concentrations of MOG35-55

peptide. In proliferation experiments, 1mCi of [H3]Thymidine

was added for the last 18 h prior harvesting liquid scintillation

counting. Alternatively, supernatants were collected after 72 h of

culture and IFN-g (BD Biosciences, San Jose, CA, USA) and IL-17

(R&D Systems, Minneapolis, MN, USA) were measured by ELISA

according to the manufacturer’s protocols.

Flow cytometry

Splenocytes and/or lymph node cells were incubated (15 min/

41C) with 10 mg/mL Fc-blocker (eBioscience) and then stained for

30 min with the following dilutions and conjugated fluoro-

chromes of a given antibody: CD4-PE (1/200), IL-17-APC

(1/150), IFN-g-APC and FOXP3-APC (1/100), (eBioscience).

For intracellular IL-17 or IFN-g staining, all cells were incubated

with PMA (50 ng/mL) and ionomycin (750 ng/mL) for 6 h in HL-

1 media at 371C and golgi blocked for the last 3 h (Golgistop, BD

Bioscience, San Diego, CA, USA). Flow cytometric data were

analyzed using Flowjo software.

Statistical analysis

Statistical significance between two means was assessed by

Mann–Whitney and unpaired t-tests. Welch correction on t-tests

was employed for sample sizeso6. Comparisons of curves were

drawn using two-way ANOVA or life tables. In total 2� 2 tables

were analyzed with Fisher’s Exact test. Statistical significance was

two tailed and set at 5%, all error bars are single SD.

Acknowledgements: The authors appreciate L. Morikawa for

excellent assistance with histopathology, and L. Han for

assistance with cytokine studies. This study was funded by

CIHR, GP is recipient of a Banting & Best fellowship award.

Conflict of interest: HMD holds shares in Afference Therapeutics

Inc., a start-up R&D company (Toronto).

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Abbreviations: DIO: diet-induced obese � hpf: high power field � IBD:

inflammatory bowel disease � LP: lamina propria � RD: regular diet �TNBS: trinitrobenzene sulfonic acid

Full correspondence: Professor H.-Michael Dosch, The Hospital For Sick

Children NMH Program, 555 University Ave, Toronto, ON, Canada M5G 1X8

Fax: 11-416-813-6255

e-mail: [email protected]

Supporting Information for this article is available at

www.wiley.vch.de/contents/jc_2040/2009/38893_s.pdf

Received: 6/9/2008

Revised: 12/6/2009

Accepted: 24/6/2009

Note added in Proof: Obesity-associated Th17 bias is systemic and

exaggerated in autoimmune target tissues, in contrast, the severe,

visceral fat-specific, lymphocytic inflammatory process of DIO mice

selectively suppresses the Th17 sublineage in that locale (Winer et al.,

Nat. Med. 2009, in press).



obesity predisposes to th17 bias

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