BackgroundCigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.Methodology and Principal FindingsThe objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.Conclusions and SignificanceThis study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.

Eosinophil degranulation of peroxidase promotes DC activation and mobilization from the intestine to LNs to induce Th2 immunity and food allergy.

Previous studies determined that the CD8؉ T-cell response elicited by recombinant adenovirus exhibited a protracted contraction phase that was associated with long-term presentation of antigen. To gain further insight into this process, a doxycycline-regulated adenovirus was constructed to enable controlled extinction of transgene expression in vivo. We investigated the impact of premature termination of transgene expression at various time points (day 3 to day 60) following immunization. When transgene expression was terminated before the maximum response had been attained, overall expansion was attenuated, yielding a small memory population. When transgene expression was terminated between day 13 and day 30, the memory population was not sustained, demonstrating that the early memory population was antigen dependent. Extinction of transgene expression at day 60 had no obvious impact on memory maintenance, indicating that maintenance of the memory population may ultimately become independent of transgene expression. Premature termination of antigen expression had significant but modest effects on the phenotype and cytokine profile of the memory population. These results offer new insights into the mechanisms of memory CD8 ؉ T-cell maintenance following immunization with a recombinant adenovirus.

We have recently reported that CD8 ؉ T-cell memory maintenance after immunization with recombinant human adenovirus type 5 (rHuAd5) is dependent upon persistent transgene expression beyond the peak of the response. In this report, we have further investigated the location and nature of the cell populations responsible for this sustained response. The draining lymph nodes were found to be important for primary expansion but not for memory maintenance, suggesting that antigen presentation through a nonlymphoid source was required. Using bone marrow chimeric mice, we determined that antigen presentation by nonhematopoietic antigenpresenting cells (APCs) was sufficient for maintenance of CD8 ؉ T-cell numbers. However, antigen presentation by this mechanism alone yielded a memory population that displayed alterations in phenotype, cytokine production and protective capacity, indicating that antigen presentation through both hematopoietic and nonhematopoietic APCs ultimately defines the memory CD8 ؉ T-cell response produced by rHuAd5. These results shed new light on the immunobiology of rHuAd5 vectors and provide evidence for a mechanism of CD8 ؉ T-cell expansion and memory maintenance that relies upon both hematopoietic and nonhematopoietic APCs. (Blood. 2011;117(4):1146-1155) IntroductionRecombinant adenovirus vectors have proven to be robust immunogens for eliciting T-cell immunity. 1-3 Vaccines derived from recombinant human adenovirus serotype 5 (rHuAd5) have displayed remarkable potency in various models prompting further investigation. To better understand the immunobiology of rHuAd5, we have been studying both the nature of the CD8 ϩ T cells elicited by these vaccines and the mechanisms of CD8 ϩ T-cell priming and memory maintenance. Immunization with rHuAd5 typically produces a sustained memory population with a protracted contraction phase, 4-8 although these kinetics may be influenced by vector configuration and route of administration. 9 The memory CD8 ϩ T-cell population is composed primarily of effector T cells (T EFF ) and effector memory T cells (T EM ), 5,6 which is indicative of a persistent viral infection. Indeed, we have recently determined that sustained, low-level antigen expression from the rHuAd5 vector plays a key role in maintaining the CD8 ϩ T-cell memory population. 10 Premature extinction of transgene expression causes pronounced CD8 ϩ T-cell contraction, but only modestly affects phenotype, suggesting that memory maintenance and phenotype may be regulated by distinct mechanisms.The relationship between memory CD8 ϩ T-cell phenotype and protective immunity remains to be fully established. T EM provide optimal immune protection against certain agents [11][12][13] ; therefore, understanding the nature of the antigen-presenting cells (APCs) involved in the generation and maintenance of CD8 ϩ T EM will provide important information for vaccine design. Dendritic cells (DCs) are thought to be critical for the induction of antiviral CD8 ϩ T-cell responses. At least 7 distinct DC populations have...