Engagement of 4-1BB Inhibits the Development of Experimental Allergic Conjunctivitis in Mice

Fukushima, Atsuki; Yamaguchi, Tomoko; Ishida, Waka; Fukata, Kazuyo; Mittler, Robert S.; Yagita, Hideo; Ueno, Hideki

doi:10.4049/jimmunol.175.8.4897

Cited by 60 publications

(53 citation statements)

References 36 publications

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“…Therefore, CD137-mediated inhibition of Th2 responses is IFN-␥ independent. This is further supported by the studies of Fukushima et al (49), which have shown that CD137 engagement by a different agonistic Ab can also inhibit both priming and effector phases of Th2-mediated experimental allergic conjunctivitis in vivo in the absence of IFN-␥. Previous studies by Zheng et al (15) have shown that CD137 costimulation induces proliferation of CD4 ϩ CD25 ϩ Treg both in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 67%

Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation

Sun¹,

Blink²,

Liu³

et al. 2006

The Journal of Immunology

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The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8+ T cells and stimulate IFN-γ production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-γ and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.

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Section: Discussionsupporting

confidence: 67%

Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation

Sun¹,

Blink²,

Liu³

et al. 2006

The Journal of Immunology

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“…The role of CD4ϩ T cells play in the development of AC has been investigated in numerous experimental settings and accumulating evidence confirms that Th2-type CD4ϩ T cells play a crucial role in the development of severe AC (9,24,28). However, the role of CD8ϩ T cells in experimental AC has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…EC is mediated by both Ag-specific IgE and Ag-specific T cells (9,12). Therefore, it could be possible that the lower eosinophil infiltration into the conjunctiva in CD8KO mice is related to altered immune responses.…”

Section: Comparison Of the Immune Responses Of Actively Immunized Wt mentioning

confidence: 99%

CD8+ T Cells Play Disparate Roles in the Induction and the Effector Phases of Murine Experimental Allergic Conjunctivitis

Fukushima

Yamaguchi

Fukuda

et al. 2006

Microbiology and Immunology

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Although CD4+ Th2 cells clearly play an essential role in the development of experimental allergic diseases, the functions CD8+ T cells may have in these diseases have been investigated less extensively and remain controversial. Here, we investigated the roles of CD8+ T cells in the development of experimental allergic conjunctivitis (EC). EC was induced in CD8α‐deficient (CD8KO) mice and wild‐type (WT) mice by active immunization with short ragweed pollen (RW) followed by challenge with RW‐containing eye drops. Alternatively, EC was induced by transferring RW‐primed splenocytes followed by RW challenge. With regard to actively immunized mice, CD8KO mice showed significantly less severe eosinophil infiltration of the conjunctiva and lower total IgE levels, although the levels of the other Igs were equivalent between the two strains. Cytokine production by cultured splenocytes also did not differ, but the WT conjunctivas showed upregulated IL‐5 and IL‐6 expression and greater upregulation of IL‐4 expression than the conjunctivas of CD8KO mice. Thus, CD8+ T cells may play a significant role during the induction phase by aiding IgE production and the generation of Th2 cytokines in the conjunctiva, thus promoting the development of EC. In contrast, splenocytes from CD8KO mice induced significantly more severe EC in WT mice than cells from WT mice. In addition, transfer of RW‐primed splenocytes induced significantly more severe eosinophil infiltration in CD8KO recipient mice. Thus, CD8+ T cells promote the development of EC during the induction phase, but suppress it during the effector phase.

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“…Costimulation through the 4-1BBL-4-1BB pathway provides cell proliferation and survival signals to T cells (6 -8) and can augment protection in tumor challenge models (9 -12). In contrast, 4-1BB stimulation can result in the triggering of suppressive T cell responses in certain models by diverse mechanisms (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Ostimulatory Signals Provide Secondary Signals To T Cells mentioning

confidence: 99%

CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand

Fuse

Bellfy

Yagita

et al. 2007

The Journal of Immunology

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Studies of costimulatory receptors belonging to the TNFR family have revealed their diverse roles in affecting different stages of the T cell response. The 4-1BB ligand (4-1BBL)/4-1BB pathway has emerged as a receptor-ligand pair that impacts not the initial priming, but later phases of the T cell response, such as sustaining clonal expansion and survival, maintaining memory CD8+ T cells, and supporting secondary expansion upon Ag challenge. Although the role of this costimulatory pathway in CD8+ T cell responses to acute viral infections has been well-studied, its role in controlling chronic viral infections in vivo is not known to date. Using the murine gammaherpesvirus-68 (MHV-68) model, we show that 4-1BBL-deficient mice lack control of MHV-68 during latency and show significantly increased latent viral loads. In contrast to acute influenza infection, the numbers of MHV-68-specific memory CD8+ T cells were maintained during latency. However, the virus-specific CD8+ T cells showed defects in function, including decreased cytolytic function and impaired secondary expansion. Thus, 4-1BBL deficiency significantly affects the function, but not the number, of virus-specific CD8+ T cells during gammaherpesvirus latency, and its absence results in an increased viral burden. Our study suggests that the 4-1BB costimulatory pathway plays an important role in controlling chronic viral infections.

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Engagement of 4-1BB Inhibits the Development of Experimental Allergic Conjunctivitis in Mice

Cited by 60 publications

References 36 publications

Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation

Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation

CD8+ T Cells Play Disparate Roles in the Induction and the Effector Phases of Murine Experimental Allergic Conjunctivitis

CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand

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