Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness

Miyahara, Nobuaki; Swanson, Bradley Jay; Takeda, Katsuyuki; Taube, Christian; Miyahara, Satoko; Kodama, Taku; Dakhama, Azzeddine; Ott, Vanessa; Gelfand, Erwin W.

doi:10.1038/nm1081

Cited by 166 publications

(176 citation statements)

References 25 publications

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“…Our data are in line with recent studies reporting on the effector role of CD8 ϩ T cells in allergic asthma (30,31) and strongly support the idea that the CD4 ϩ Th2 dogma in allergic diseases should be revisited (7). However, although the results presented come from a representative mouse model, studies in humans are required to confirm the hypothesis that CD8 ϩ T cells are involved in the development of AD skin lesions.…”

Section: Discussionsupporting

confidence: 91%

Skin-Infiltrating CD8+ T Cells Initiate Atopic Dermatitis Lesions

Hennino

Vocanson

Toussaint

et al. 2007

The Journal of Immunology

103

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Skin lesions in the allergic form of atopic dermatitis (AD) are induced by allergen-specific T cells that infiltrate the skin at the site of allergen exposure. Although Th2-type CD4+ T cells appear to be crucial in AD pathophysiology, little is known about the contribution of CD8+ T cells in the development of the allergic skin inflammation. In the present study, we have analyzed the respective role of CD8+ and CD4+ T cells in the development of AD skin lesions in a mouse model of allergen-induced AD. In sensitized mice, CD8+ T cells are rapidly and transiently recruited to the allergen-exposed site and initiate the inflammatory process leading to skin infiltration with eosinophils and Th1/Th2-producing cells. CD8+ T cell-depleted mice show no inflammation, demonstrating that these cells are mandatory for the development of AD. In contrast, CD4+ T cell-depleted mice develop a severe form of eczema. Furthermore, adoptive transfer of CD8+ T cells from sensitized mice into naive recipient mice leads to skin inflammation soon after allergen exposure. These data indicate that allergen-primed CD8+ T cells are required for the development of AD-like lesions in mice.

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Section: Discussionsupporting

confidence: 91%

Skin-Infiltrating CD8+ T Cells Initiate Atopic Dermatitis Lesions

Hennino

Vocanson

Toussaint

et al. 2007

The Journal of Immunology

103

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“…Previous studies have demonstrated the presence of CD8ϩ T cells producing IL-4 in bronchoalveolar lavage fluid from patients with SSc, and this finding was correlated with the development of lung fibrosis (23). In addition, CD8ϩ Teff cells were shown to be a source of IL-13 in a mouse model of airway hyperresponsiveness and airway inflammation (46), supporting the idea that CD8ϩ T cells can play important roles in type 2-driven immune responses. Analysis of peripheral blood CD8ϩ T cells indicates that not only is the number of IL-13ϩ Teff cells increased, but the total number of circulating Teff cells in the peripheral blood of SSc patients is also elevated compared with that in normal donors.…”

Section: Discussionmentioning

confidence: 59%

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Fuschiotti¹,

Medsger²,

Morel³

2009

Arthritis & Rheumatism

104

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Objective. T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell-derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.Methods. To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4؉ and CD8؉ T cell subsets to produce cytokines following in vitro activation.Results. High levels of the profibrotic type 2 cytokine interleukin-13 (IL-13) were produced following activation of peripheral blood effector CD8؉ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4؉ T cells showed a lower and more variable level of IL-13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients. Conclusion. Dysregulated IL-13 production by effector CD8؉ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.

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“…In different model systems, CD8 T cell responses are known to require CD4 T cell help and may explain this result (2,18). Interestingly, CD8 T cells have been shown to play a role in airway inflammation and hyperresponsiveness (32,38) and hence their reduced numbers in the lungs may have contributed to the reduction in inflammation we observed. On the other hand, the remaining CD8 T cells might be required for the continued eosinophilic inflammation that we observed in the absence of CD4ϩ cells, and this needs to be investigated in future studies depleting this subset of cells.…”

Section: Discussionmentioning

confidence: 74%