IL‐4 Differentiates Naive CD8+ T Cellsto a “Th2‐Like” Phenotype:A Link Between Viral Infections & Bronchial Asthma

Abstract

Viral infections of the lung have been postulated to be a major factor in the etiology of bronchial asthma, a disease characterized by eosinophilic inflammation of the airways. In addition, upper respiratory tract infection in asthmatic individuals results in an exacerbation of the disease. Nevertheless, the mechanisms by which viral infection leads to disease exacerbation are poorly understood. CD8+ T cells play an important role in the host defense responses against viral infection, although to date, there are no reports to suggest that CD8+ T cells play any role in eosinophil recruitment. In the present study, we report that CD8+ T cells activated by either immobilized CD3 mAb or specific antigen can switch to a phenotype that produces Th2 cytokines and secretes less IFN-gamma. Moreover, in vivo, if a lung mucosal Th2 immune response exists, then antigen-specific activation of CD8 cells results in the development of lung eosinophilic inflammation mediated by the secretion of IL-5 from CD8+ T cells. These results may explain the link between viral infections and bronchial asthma, as this IL-4-dependent switch to CD8+ T cells to IL-5 secretion may not only exacerbate asthma by recruiting eosinophils into the lungs, but the impaired IFN-gamma production may also lead to delayed viral clearance.

Flt-3 Ligand Reverses Late Allergic Response and Airway Hyper-Responsiveness in a Mouse Model of Allergic Inflammation

“…Augmented levels of IL-4 in BALF (42) and increased expression of IL-4 mRNA in BAL cells (43,44) have been recognized in patients with allergic inflammation. In murine models, IL-4 has been reported to be important for the development of allergic airway inflammation (45)(46)(47) and AHR (48,49). In our study we observed a significant decrease in BALF IL-4 levels.…”

Modulation of Inhaled Antigen-Induced IgE Tolerance by Ongoing Th2 Responses in the Lung

“…ϩ Th2 recall responses to sensitized OVA were able to redirect the CD8 antiviral peptide response to the production of IL-5 and subsequent eosinophilia (76,77). Also, it is clear that Th2 sensitization can occur in the lung even in the presence of significant IFN-␥ concentrations (78 -80).…”

Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma

“…Monoclonal antibody 3B9 inhibited IL-4-dependent events, including IL-5 synthesis, T H 2 cell activation and IgE upregulation. The humanized pascolizumab MoAb retained the 10 (27-139) 3 (370-1070) 6 (53-272) 3 (80-231) 4 IC 50 = 50% inhibitory concentration; IC 25 = 25% inhibitory concentration. *Mean (range) n .…”

“…Interleukin (IL)-4 is thought to be a key cytokine in the early stages of asthma because of its role in regulating B-cell isotype switching to immunoglobulin (Ig)E production, eosinophil chemotaxis and the development of effector T-cell responses [1,2], Interleukin-4 is produced by T lymphocytes, activated mast cells and basophils. Along with other cytokines (including IL-5 and IL-13), IL-4 can induce the development of allergic inflammatory diseases and can promote the differentiation of undifferentiated helper T cells (T H 0) into type 2 helper T cells (T H 2) [3,4]. These T H 2 cells, in turn, secrete a pattern of cytokines including IL-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony-stimulating factor [5] that initiate and perpetuate the asthmatic inflammatory response leading to airway inflammation, obstruction and hyperresponsiveness characteristic of chronic asthma [6].…”