CD28 Interactions with Either CD80 or CD86 Are Sufficient to Induce Allergic Airway Inflammation in Mice

Abstract

Previous studies have shown that the pan CD28/cytotoxic T lymphocyte antigen (CTL)A-4 antagonist CTLA4 immunoglobulin (Ig) inhibits eosinophilic airway inflammation in Schistosoma mansoni-sensitized and airway-challenged mice. In the present study, the importance of CD28 as well as the individual roles of CD80 and CD86 were examined in this system using wild-type and CD28 knockout (KO) mice. Unlike wild-type controls, CD28KO mice did not produce systemic IgE or eosinophilic airway inflammation after antigen challenge. However, a lymphocytic infiltrate and continued production of interferon-gamma was observed in these animals. Thus, CD28 is not essential for the initial recruitment of lymphocytes into antigen-challenged airways but critically regulates the allergic T-helper 2 phenotype. We next determined by polymerase chain reaction and flow cytometry that CD80 and CD86 molecules are constitutively expressed in the naive murine lung and on eosinophils in the allergic lung, suggesting a potential important role for both ligands in the development of asthma. Combined anti-CD80/anti-CD86 treatment throughout the antigen challenge period fully blocked the development of allergic airways, whereas a partial reduction was observed in mice treated with either anti-CD80 or anti-CD86 antibody alone. However, only anti-CD86 blocked systemic IgE production. Therefore, signaling through either CD80 or CD86 is sufficient to generate a partial local allergic response, whereas CD86 costimulation is essential to induce systemic allergic (IgE) reactions. Finally, combined anti-B7 monoclonal antibody treatment after sensitization reduced airway eosinophilia and interleukin (IL)-4/IL-5 cytokine secretion consistent with an ongoing role for CD28/B7 interactions in the effector phase of the disease. These results emphasize the importance of differential B7 expression on different cells and in different organs on subsequent CD28/B7-mediated immune events, including the potential for CD28/B7 blockade in the treatment of atopic airway disease in people.

Airway Eosinophils Accumulate in the Mediastinal Lymph Nodes but Lack Antigen-Presenting Potential for Naive T Cells

“…In our experiments, an accumulation of CCR3 ϩ eosinophils in draining lymph nodes of the lung was indeed observed at a time point when eosinophils were accumulating in the allergically inflamed lung, suggesting that eosinophils were migrating from the lung to the lymph nodes where T cells are recirculating. These findings are consistent with earlier reports by other groups and indeed suggest some Agpresenting function (7)(8)(9)(10). In our study, in addition to the presence of eosinophils at the site of T cell encounter, BALF eosinophils weakly expressed MHCII and expressed high levels of costimulatory molecules CD80 and ICAM-1.…”

CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma

“…Therefore, we determined whether postchallenge CpG-ODN treatment also influenced B7.1 and B7.2 expression in the lung. It has been suggested that many cells in murine lungs can potentially process and/or present Ag, including "professional" APCs (B cells, alveolar macrophages, and dendritic cells) and nontraditional APCs (epithelial cells, eosinophils) (28). However, it has not yet been determined which APC or combination of APCs plays a dominant role in T lymphocyte activation in human asthma or mouse models of asthma.…”

Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation

“…Although we found that airway eosinophilia was completely abrogated, the number of BALF T cells induced by OVA aerosol was identical between CD28 -/-and wild-type mice. By analogy, recent work in a S. mansoni-induced model of airway inflammation has shown that CD28 deficiency abolishes airway eosinophilia but does not affect the initial recruitment of T cells into Ag-challenged airways (39). The absence of airway eosinophilia in CD28 -/-mice could be due to defective Th2 priming or to defective generation of effector function in Th2 cells during challenge of the airways.…”