In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation

Seshasayee, Dhaya; Lee, Wyne P.; Zhou, Meijuan; Shu, Jean; Suto, Eric; Zhang, Juan; Diehl, L; Austin, Cary D.; Meng, Yaqi; Tan, Martha; Bullens, Sherron; Seeber, Stefan; Fuentes, María E.; Labrijn, Aran F.; Graus, Y.; Miller, Lisa; Schelegle, Edward S.; Hyde, Dallas M.; Wu, Lawren C.; Hymowitz, S.G.; Martin, Flavius

doi:10.1172/jci33559

Cited by 191 publications

(175 citation statements)

References 35 publications

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“…The innate cytokines TSLP, IL-33, and IL-25 have been shown to be required for optimal Th2 priming through their ability to upregulate OX40L expression on DC (13,17,34). Experiments in TSLPR KO mice and using OX40L-blocking Abs showed that the TSLP-OX40L axis was not critical for the priming of IL-4-producing T cells, a result that is consistent with other studies using helminth parasites including live N. brasiliensis (19,40).…”

Section: Discussionsupporting

confidence: 85%

“…OX40L expression on DC is induced by innate cytokines, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. Blockade of OX40L results in markedly diminished allergic inflammation in models of allergic airway, skin, and gastrointestinal disease (13,16,17); however, OX40/OX40L deficiency does not block IL-4 production during parasite infections (18,19). In addition, it is not yet firmly established whether OX40-OX40L is a true Th2-polarizing signal or whether its function is mainly costimulatory (20,21).…”

mentioning

confidence: 99%

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Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Connor

Tang

Camberis

et al. 2014

The Journal of Immunology

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Dendritic cells (DC) are critical for the initiation of immune responses; however, their role in priming IL-4–producing Th2 cells in vivo is not fully understood. We used a model of intradermal injection with fluorescent-labeled, nonviable larvae from the helminth parasite nonviable Nippostrongylus brasiliensis L3 larvae (Nb), a strong inducer of Th2 responses, together with IL-4–GFP reporter mice that enable a sensitive detection of IL-4 production to examine the contribution of DC to the priming of IL-4–producing CD4+ T cells in vivo. We found that parasite material is taken up by two distinct DC populations in draining lymph nodes: a mostly CD11cintMHC class II (MHCII)hiCD11b+Ly6C− dermal DC population and a CD11chiMHCIIintCD11b+Ly6C+ monocyte-derived DC population. After Nb treatment, these two DC populations appeared in the draining lymph nodes in comparable numbers and with similar kinetics; however, treatment with pertussis toxin blocked the migration of dermal DC and the priming of IL-4–producing T cells, but only partially affected monocyte-derived DC numbers. In line with this observation, transfer of OVA-loaded CD11cintMHCIIhi DC from Nb-treated mice into naive hosts could sensitize OVA-specific CD4+ T cells to IL-4 production, whereas transfer of CD11cintMHCIIhi DC from naive mice, or CD11chiMHCIIint DC from Nb-treated or naive mice, induced CD4+ T cell expansion but no IL-4 production. Phenotypic analysis of Nb-loaded CD11cintMHCIIhi DC revealed expression of programmed death ligand 2, CD301b, IFN regulatory factor 4, and moderate upregulation of OX40 ligand. However, thymic stromal lymphopoietin and OX40 ligand were not required for Th2 priming. Thus, our data suggest that appropriate stimuli can induce DC to express the unique signals sufficient to direct CD4+ T cells to Th2 differentiation.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Connor

Tang

Camberis

et al. 2014

The Journal of Immunology

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“…We cannot rule out indirect effects on the T cells, e.g., via up-regulation the expression of OX40L on skin DCs that present antigen to infiltrating T cells at the site of challenge. In this regard, in vivo blockade of OX40 ligand inhibits TSLP driven atopic inflammation in lung and skin, including Th2 inflammatory cell infiltration and cytokine secretion (28).…”

Section: Discussionmentioning

confidence: 99%

TSLP acts on infiltrating effector T cells to drive allergic skin inflammation

Oyoshi²,

Garibyan³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

231

223

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Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR ؊/؊ mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR ؊/؊ mice in response to OVA was normal. Skin dendritic cells from TSLPR ؊/؊ mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4 ؉ T cells from TSLPR ؊/؊ mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

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“…Costimulatory signals may perform several functions, such as augmenting production of interleukin (IL)-2 or the archetypal growth factor, promoting cell cycle progression, inducing effector cytokine production, such as those of the Th1 and Th2 type, suppressing cell death by altering bcl-2 and caspase protein function, and enhancing memory T cell development (4,5). Advances in our understanding of T cell costimulatory molecules have provided a vast array of novel approaches in preventing autoimmune, infectious, inflammatory, and tumorous diseases (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%