Allergen-Induced CD4+ T Cell Cytokine Production within Airway Mucosal Dendritic Cell–T Cell Clusters Drives the Local Recruitment of Myeloid Effector Cells

Veres, Tibor Z.; Kopcsányi, Tamás; Panhuys, Nicholas J. Van; Gerner, Michael Y.; Liu, Zhiduo; Rantakari, Pia; Dunkel, Johannes; Miyasaka, Masayuki; Salmi, Marko; Jalkanen, Sirpa; Germain, Ronald N.

doi:10.4049/jimmunol.1601448

Cited by 16 publications

(17 citation statements)

References 59 publications

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“…The hallmarks of Th2-type responses in asthma are eosinophilic airway inflammation with mucus secretion, airway remodeling, and hyperreactivity. 8,9 IL-5 and IL-13 are critical for the pathophysiology of asthma. IL-5 has multifaceted roles, including the direct activation of eosinophils, influencing adhesion and inducing chemotaxis and inflammatory mediator synthesis.…”

Section: Introductionmentioning

confidence: 99%

A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma

Liu

et al. 2017

Cell Mol Immunol

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Programmed death one homolog (PD-1H) is a cell surface molecule of the B7/CD28 immune modulatory gene family. Although PD-1H has been shown to function as a coinhibitory receptor on T cells to limit naive T-cell activation and proliferation, its role in the regulation of the T-cell response to allergens is unknown. We report here that genetic ablation or blockade of PD-1H drastically promotes pulmonary inflammation with massive accumulation of eosinophils in a mouse model of experimental asthma, indicating a suppressive function of PD-1H in allergic inflammation. The loss of PD-1H led to elevated production of both innate cytokines (IL-6, MCP-1 and TNFα) and Th2 cytokines (IL-5 and IL-13) in the lung, indicating a critical role of PD-1H in suppressing the production of airway inflammatory cytokines. In addition, the loss of PD-1H also impaired the expansion of systemic and pulmonary regulatory T cells during asthma induction. These findings support a critical role of intrinsic PD-1H in the regulation of inflammatory responses to allergens. Finally, we showed that treatment with a PD-1H agonistic monoclonal antibody reduced the severity of asthma, which was accompanied by suppressed lung inflammation. Our findings support PD-1H as a potential target and suggest a possible strategy for the treatment of allergic asthma in humans.

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Section: Introductionmentioning

confidence: 99%

A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma

Liu

et al. 2017

Cell Mol Immunol

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“…Based on our finding that the suppressive capacity of eosinophils depends on their contact with T cells ( Figure 3B), we next considered the possibility that professional APCs may act as a scaffolding to facilitate eosinophil-T cell contact. This assumption was based on our previous demonstration that T cells make stable and durable contact with lung-resident DCs (23) and the fact that eosinophils can mediate the recruitment and accumulation of DCs in asthma models (24,25). To this end, we compared in a pairwise fashion the formation of eosinophil-T cell complexes in cocultures of B6 T cells stimulated with BALB/c bone marrow-derived DCs (BMDCs) or anti-CD3/CD28 agonistic antibodies.…”

Section: Figure 1 Th1 Polarization Of the Lung Allograft (A)mentioning

confidence: 99%

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

et al. 2019

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It has been demonstrated by us as well as others that eosinophils may alter their phenotype and function based on the local environment (7, 9, 10). Since costimulation plays a critical role in T cell cytokine production and environmental polarization (11, 12), we examined the possibility that eosinophils may lose their tolerogenic properties in the absence of CSB immunosuppression. Cytokine expression was examined in BALB/c (H2 d) lung allografts transplanted into fully MHC-mismatched C57BL/6 (B6) (H2 b) recipient mice. In the absence of immunosuppression, lung allografts had higher levels of Th1-polarizing cytokines IFN-γ and TNF-α than did CSB-treated accepting lung grafts (Figure 1A). Limited amounts of Th2-polarizing cytokines IL-4, IL-13, IL-33, and GM-CSF were evident in lung allografts treated with or without CSB immunosuppression (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.128241DS1). We next evaluated lung-resident eosinophils from both CSB-treated and nonimmunosuppressed grafts. Based on a previously identified eosinophil polarization phenotype (7), we noted higher levels of Th1-defining (or E1-defining) features, such as CXCL9, CXCL10, CXCL11, and iNOS in eosinophils isolated from rejecting compared with CSB-treated lung allografts (Figure 1A). In no group was Th2 (or E2) polarization of eosinophils detected (Supplemental Figure 1A). Flow cytometric characterization demonstrated an absence of MHC II and costimulatory molecules such as CD80, CD86, and CD40. However, there were high levels of recipient-derived MHC I (H2K b), PD-L1, and CD101 on lung-resident eosinophils in the absence of CSB (Figure 1B). Notably, we did not detect BALB/c-derived H2 d-MHC on graft-resident eosinophils, indicating a lack of "cross-dressing" or antigen swapping for donor derived-antigens (ref. 13 and Supplemental Figure 1B). Thus, while eosinophils from rejecting lungs resembled those from accepting lungs in some aspects, we did observe some differences. It is thus possible that in the absence of immunosuppression, eosinophils may contribute to graft rejection rather than acceptance, specifically because CD101 expression has been previously associated with an inflammatory eosinophil subtype (14). In order to evaluate this directly, we conditionally depleted eosinophils from B6 iPHIL mice, in which the diphtheria toxin (DT) receptor is expressed under the control of the eosinophil peroxidase promoter (Supplemental Figure 1C and ref. 15). DT-treated mice or saline-injected controls were challenged with a BALB/c lung allograft in the absence of immunosuppression. Surprisingly, mice depleted of eosinophils had higher grades of rejection (Figure 1C), increased numbers of lung-resident T lymphocytes, increased rates of T cell proliferation, and increased effector cell differentiation by day 4 after engraftment (Figure 1D). These patterns of T lymphocyte activation and infiltration were especially prominent for CD8 + T cells. CD4 + T cell proliferation did ...

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“…Thus, the removal of apoptotic neutrophils from swarming clusters that we supposedly observed in the present study evidently inhibited swarm amplification. Due to their low motility, IE-DCs are unlikely to migrate to the draining lymph nodes, but they can also be involved in the activation of T cells in the periphery (8). The production of IL-2 by CD103 + lung DCs was recently shown to play a fundamental role in the suppression of the Th17/IL-17 proinflammatory response to A. fumigatus (9).…”

Section: Discussionmentioning

confidence: 99%

“…Conducting airway IE-DCs were characterized for the first time almost 30 years ago as MHCII-bearing cells with the "classical dendritic cell morphology" that formed the dense network in the airways (40). Later investigations confirmed that at steady state, these cells mostly express CD11c (8). Here, we show that upon A. fumigatus conidia-induced inflammation development, some CD11c − APCs (MHCII + CD11c − cells with the morphology of IE-DCs) infiltrate the conducting airway wall.…”

Section: Discussionmentioning

confidence: 99%

“…In the airways, mucosal DCs form a network that permits the sensing of inhaled pathogens such as A. fumigatus conidia (5,6). DCs of the airway mucosa function as professional antigen-presenting cells (APCs) and can sample airborne antigens and activate the adaptive immune response, either systemically in the draining lymph nodes or locally in the periphery (7,8). Beyond activation of adaptive immunity, tissue-resident DCs control the local innate immune response that is crucial in acute inflammation (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Murine Intraepithelial Dendritic Cells Interact With Phagocytic Cells During Aspergillus fumigatus-Induced Inflammation

et al. 2020

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Allergen-Induced CD4+ T Cell Cytokine Production within Airway Mucosal Dendritic Cell–T Cell Clusters Drives the Local Recruitment of Myeloid Effector Cells

Cited by 16 publications

References 59 publications

A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma

A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

Murine Intraepithelial Dendritic Cells Interact With Phagocytic Cells During Aspergillus fumigatus-Induced Inflammation

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