Objectives: Exosomes are extracellular vesicles released from various inflammatory cells, such as T cells, B cells, dendritic cells (DCs), and mast cells, which have been implicated in the modulation of immune response in asthma. This study aimed to investigate whether exosomes from DCs activated by thymic stromal lymphopoietin (TSLP) play a role in T-helper cell differentiation through the OX40 ligand (OX40L). Methods: Serum samples from patients with asthma were collected to measure the levels of OX40L, T-helper type 1 (Th1) cytokine interferon (IFN)-γ, and T-helper type 2 (Th2) cytokine interleukin (IL)-4 by enzyme-linked immunosorbent assay (ELISA). Exosomes were isolated from TSLP-activated DCs and co-cultured with CD4+ T cells. Western blot and ELISA assays were used to measure the levels of OX40L, IFN-γ, and IL-4 in DCs and CD4+ T cells. Flow cytometry was applied to detect Th1 and Th2 cells. Results: OX40L and IL-4 were increased and IFN-γ was decreased in serum from asthmatic patients compared with healthy controls. TSLP induced DCs to express OX40L in released exosomes, which could promote proliferation of CD4+ T cells, elevate the level of IL-4, and promote Th2 differentiation. Conclusion: Blockade of OX40L in DC-derived exosomes could inhibit exosome-mediated CD4+ T proliferation and Th2 differentiation.

1.
Bousquet
J
: Global initiative for asthma (GINA) and its objectives. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
2000
;30 Suppl 1:2-5.
2.
Hamid
Q
,
Tulic’
MK
,
Liu
MC
,
Moqbel
R
.
Inflammatory cells in asthma: mechanisms and implications for therapy
.
J Allergy Clin Immunol
.
2003
Jan
;
111
(
1
Suppl
):
S5
12
.
[PubMed]
0091-6749
3.
Kim
Y
,
Lee
S
,
Kim
YS
,
Lawler
S
,
Gho
YS
,
Kim
YK
, et al.
Regulation of Th1/Th2 cells in asthma development: a mathematical model
.
Math Biosci Eng
.
2013
Aug
;
10
(
4
):
1095
133
.
[PubMed]
1547-1063
4.
Yamane
H
,
Paul
WE
.
Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets
.
Immunol Rev
.
2013
Mar
;
252
(
1
):
12
23
.
[PubMed]
0105-2896
5.
Kato
A
,
Favoreto
S
 Jr
,
Avila
PC
,
Schleimer
RP
.
TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells
.
J Immunol
.
2007
Jul
;
179
(
2
):
1080
7
.
[PubMed]
0022-1767
6.
Qian
WL
.
Thymic stromal lymphopoietin and allergic dermatoses
.
Thymic Stromal Lymphopoietin
;
2010
.
7.
Melum
GR
,
Farkas
L
,
Scheel
C
,
Van Dieren
B
,
Gran
E
,
Liu
YJ
, et al.
A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa
.
J Allergy Clin Immunol
.
2014
Sep
;
134
(
3
):
613
621.e7
.
[PubMed]
0091-6749
8.
Wang
YH
,
Ito
T
,
Wang
YH
,
Homey
B
,
Watanabe
N
,
Martin
R
, et al.
Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells
.
Immunity
.
2006
Jun
;
24
(
6
):
827
38
.
[PubMed]
1074-7613
9.
Ito
T
,
Wang
YH
,
Duramad
O
,
Hori
T
,
Delespesse
GJ
,
Watanabe
N
, et al.
TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand
.
J Exp Med
.
2005
Nov
;
202
(
9
):
1213
23
.
[PubMed]
0022-1007
10.
Kaur
D
,
Brightling
C
.
OX40/OX40 ligand interactions in T-cell regulation and asthma
.
Chest
.
2012
Feb
;
141
(
2
):
494
9
.
[PubMed]
0012-3692
11.
Li
DQ
,
Zhang
L
,
Pflugfelder
SC
,
De Paiva
CS
,
Zhang
X
,
Zhao
G
, et al.
Short ragweed pollen triggers allergic inflammation through Toll-like receptor 4-dependent thymic stromal lymphopoietin/OX40 ligand/OX40 signaling pathways
.
J Allergy Clin Immunol
.
2011
Dec
;
128
(
6
):
1318
1325.e2
.
[PubMed]
0091-6749
12.
Meng
Q
,
Liu
X
,
Li
P
,
He
L
,
Xie
J
,
Gao
X
, et al.
The influence of house dust mite sublingual immunotherapy on the TSLP-OX40L signaling pathway in patients with allergic rhinitis
.
Int Forum Allergy Rhinol
.
2016
Aug
;
6
(
8
):
862
70
.
[PubMed]
2042-6976
13.
Sastre
B
,
Cañas
JA
,
Rodrigo-Muñoz
JM
,
Del Pozo
V
.
Novel Modulators of Asthma and Allergy: exosomes and MicroRNAs
.
Front Immunol
.
2017
Jul
;
8
:
826
.
[PubMed]
1664-3224
14.
Théry
C
,
Duban
L
,
Segura
E
,
Véron
P
,
Lantz
O
,
Amigorena
S
.
Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes
.
Nat Immunol
.
2002
Dec
;
3
(
12
):
1156
62
.
[PubMed]
1529-2908
15.
Thery
C
,
Amigorena
S
,
Raposo
G
,
Clayton
A
.
Isolation and characterization of exosomes from cell culture supernatants and biological fluids.
Current protocols in cell biology
2006
;Chapter 3:Unit 3.22.
16.
Gaurav
R
,
Agrawal
DK
.
Clinical view on the importance of dendritic cells in asthma
.
Expert Rev Clin Immunol
.
2013
Oct
;
9
(
10
):
899
919
.
[PubMed]
1744-666X
17.
Walsh
KP
,
Mills
KH
.
Dendritic cells and other innate determinants of T helper cell polarisation
.
Trends Immunol
.
2013
Nov
;
34
(
11
):
521
30
.
[PubMed]
1471-4906
18.
Hivroz
C
,
Chemin
K
,
Tourret
M
,
Bohineust
A
.
Crosstalk between T lymphocytes and dendritic cells
.
Crit Rev Immunol
.
2012
;
32
(
2
):
139
55
.
[PubMed]
1040-8401
19.
Lombardi
V
,
Singh
AK
,
Akbari
O
.
The role of costimulatory molecules in allergic disease and asthma
.
Int Arch Allergy Immunol
.
2010
;
151
(
3
):
179
89
.
[PubMed]
1018-2438
20.
Kopecka
J
,
Rozkova
D
,
Sediva
A
.
Plasmacytoid DCs, exposed to TSLP in synergy with TLR ligands, acquire significant potential towards Th2 polarization
.
Med Sci Monit Basic Res
.
2013
Dec
;
19
:
291
9
.
[PubMed]
2325-4394
21.
Zhang
Y
,
Zhou
X
,
Zhou
B
.
DC-derived TSLP promotes Th2 polarization in LPS-primed allergic airway inflammation
.
Eur J Immunol
.
2012
Jul
;
42
(
7
):
1735
43
.
[PubMed]
0014-2980
22.
Fujita
Y
,
Yoshioka
Y
,
Ito
S
,
Araya
J
,
Kuwano
K
,
Ochiya
T
.
Intercellular communication by extracellular vesicles and their microRNAs in asthma
.
Clin Ther
.
2014
Jun
;
36
(
6
):
873
81
.
[PubMed]
0149-2918
23.
Carroll-Portillo
A
,
Cannon
JL
,
te Riet
J
,
Holmes
A
,
Kawakami
Y
,
Kawakami
T
, et al.
Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation
.
J Cell Biol
.
2015
Aug
;
210
(
5
):
851
64
.
[PubMed]
0021-9525
24.
Dudeck
A
,
Suender
CA
,
Kostka
SL
,
von Stebut
E
,
Maurer
M
.
Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function
.
Eur J Immunol
.
2011
Jul
;
41
(
7
):
1883
93
.
[PubMed]
0014-2980
25.
Mazzeo
C
,
Cañas
JA
,
Zafra
MP
,
Rojas Marco
A
,
Fernández-Nieto
M
,
Sanz
V
, et al.
Exosome secretion by eosinophils: A possible role in asthma pathogenesis
.
J Allergy Clin Immunol
.
2015
Jun
;
135
(
6
):
1603
13
.
[PubMed]
0091-6749
26.
Cañas
JA
,
Sastre
B
,
Mazzeo
C
,
Fernández-Nieto
M
,
Rodrigo-Muñoz
JM
,
González-Guerra
A
, et al.
Exosomes from eosinophils autoregulate and promote eosinophil functions
.
J Leukoc Biol
.
2017
May
;
101
(
5
):
1191
9
.
[PubMed]
0741-5400
27.
Admyre
C
,
Bohle
B
,
Johansson
SM
,
Focke-Tejkl
M
,
Valenta
R
,
Scheynius
A
, et al.
B cell-derived exosomes can present allergen peptides and activate allergen-specific T cells to proliferate and produce TH2-like cytokines
.
J Allergy Clin Immunol
.
2007
Dec
;
120
(
6
):
1418
24
.
[PubMed]
0091-6749
28.
Wahlgren
J
,
Karlson
TL
,
Glader
P
,
Telemo
E
,
Valadi
H
.
Activated human T cells secrete exosomes that participate in IL-2 mediated immune response signaling
.
PLoS One
.
2012
;
7
(
11
):
e49723
.
[PubMed]
1932-6203
29.
Nazimek
K
,
Ptak
W
,
Nowak
B
,
Ptak
M
,
Askenase
PW
,
Bryniarski
K
.
Macrophages play an essential role in antigen-specific immune suppression mediated by T CD8⁺ cell-derived exosomes
.
Immunology
.
2015
Sep
;
146
(
1
):
23
32
.
[PubMed]
0019-2805
30.
Yu
X
,
Huang
C
,
Song
B
,
Xiao
Y
,
Fang
M
,
Feng
J
, et al.
CD4+CD25+ regulatory T cells-derived exosomes prolonged kidney allograft survival in a rat model
.
Cell Immunol
.
2013
Sep-Oct
;
285
(
1-2
):
62
8
.
[PubMed]
0008-8749
31.
Naslund
TI
,
Gehrmann
U
,
Qazi
KR
,
Karlsson
MC
,
Gabrielsson
S
: Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. Journal of immunology (Baltimore, Md : 1950)
2013
;190:2712-2719.
32.
Tkach
M
,
Kowal
J
:
Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes.
2017
;36:3012-3028.
33.
Ohshima
Y
,
Yang
LP
,
Uchiyama
T
,
Tanaka
Y
,
Baum
P
,
Sergerie
M
, et al.
OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors
.
Blood
.
1998
Nov
;
92
(
9
):
3338
45
.
[PubMed]
0006-4971
34.
Li
F
,
Wang
Y
,
Lin
L
,
Wang
J
,
Xiao
H
,
Li
J
, et al.
Mast Cell-Derived Exosomes Promote Th2 Cell Differentiation via OX40L-OX40 Ligation
.
J Immunol Res
.
2016
;
2016
:
3623898
.
[PubMed]
2314-7156
35.
Admyre
C
,
Grunewald
J
,
Thyberg
J
,
Gripenbäck
S
,
Tornling
G
,
Eklund
A
, et al.
Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid
.
Eur Respir J
.
2003
Oct
;
22
(
4
):
578
83
.
[PubMed]
0903-1936
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