CD8 T Cells Promote the Resolution of Prolonged Airway Inflammation in a Murine Model of Asthma
J Tong, CM Ferreira, IO Gordon, BS Clay, HS Bandukwala, J Krishnan, AN Husain, J Solway, A Sperling. University of Chicago, Chicago, IL
Background: Human asthma is characterized by persistent airway inflammation, mucus production, and airway hyperreactivity (AHR). The role of CD8+ T cells in the chronic airway inflammation of asthma is controversial. Previous reports have suggested that CD8 effector (CD62LlowCD44hi), and not CD8 central memory (CD62LhiCD44hi) T cells mediate airway inflammation and AHR. Our previous studies revealed that in a murine model of asthma, mice that received Fas-deficient T cells developed a persistent phase of airway inflammation, mucus production, and AHR. Interestingly, although the acute phase of inflammation was dominated by CD4 effector cells, during the persistent phase we found an increase in the number of CD8+ T cells in the BAL, lungs and spleens. These CD8+ cells expressed activation markers that are characteristic of effector T cells, and therefore may actually be driving the active persistent airway inflammation.
Design: 1) To determine whether there are more CD8+ T cells in airways of asthma patients, endobronchial biopsies were collected from 5 severe persistent asthma patients and immunohistochemistry was performed to indirectly determine the presence of CD8+ and CD4+ T cells. 2) To investigate the role of CD8+ T cells in our murine model of prolonged airway inflammation, T cells were adoptively transferred into Rag-/- mice intravenously at day -15. Reconstituted mice were sensitized and challenged with allergen at days -14, -7 and 0, respectively. At the end of the acute phase, CD8+ T cells were depleted in vivo by I.P. injection of anti-CD8 depletion antibody or control Ig for 4 consecutive days after the last challenge. Mice were sacrificed for study two weeks later to investigate inflammation resolution.
Results: Severe persistent asthma patients appear to have more airway CD8+ T cells than CD4+ T cells. In addition, in the absence of CD8+ T cells, inflamed mice had a prolonged eosinophilia, mucus production, and peribronchial and perivascular inflammation. Furthermore, cytokine analysis showed that CD8+ T cells produced IFN-γ which promoted the resolution of the airway inflammation.
Conclusions: Our study suggests that endogenous effector CD8+ T cells in the airways have a promoting rather than inhibitory effect on the resolution of persistent airway inflammation
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 243, Monday Morning