© 2002 American Thoracic Society
Dendritic Cells in the Mycobacterial Granuloma Are Involved in Acquired ImmunityPulmonary Division University Hospital of Geneva Geneva, Switzerland Today, one third of the global population is infected latently by Mycobacterium tuberculosis and about three million people die every year of tuberculosis. In view of this resurgence of tuberculosis, research efforts have intensified to understand better the host defense mechanisms against this mycobacterial disease. Granuloma formation is the hallmark of infection by mycobacteria, and a number of other human diseases. However, the role of granulomas in the immune defense against mycobacterial infection is still poorly understood (1). Is this phenomenon simply a functionless byproduct of chronic infection? Do the granulomas have a role in the induction and maintenance of immune responses against mycobacteria? Or, on the contrary, does the granuloma subserve the pathogen, allowing it to remain undetected and survive within the pulmonary tissues? In this issue of AJRCCM (pp. 1640–1646), Tsuchiya and coworkers (2) present data that shed new light on what might be the important functional purpose of granulomas in the immune response to mycobacteria and, possibly, other chronic infections. In this study, granuloma formation was elicited by the injection of heat-killed Mycobacterium bovis bacillus Calmette-Guérin (BCG) in a rat model. The authors characterized dendritic cells within the granulomas by immunohistochemistry, isolated dendritic cells from the granulomatous lung, and induced PPD-specific T cell responses using these isolated dendritic cells. The results demonstrate that dendritic cells are not only involved in the formation of the BCG-induced granulomas, but are also capable of inducing acquired (antigen-specific) immune responses against the mycobacteria. Antigen-presenting cells in the lungs are essentially represented by submucosal and interstitial dendritic cells and alveolar macrophages, residing mostly in the air spaces (3, 4). Both dendritic cells and macrophages create a tight surveillance network in lung tissue that captures particulate or soluble antigens at the site of pathogen entry. Although macrophages are the predominant cell type in the airways, dendritic cells are much more potent antigen-presenting cells. After activation by microbial signals, dendritic cells migrate to the local lymphatic organs, where they present the processed antigens to both naive and primed T cells (5). Aside from their crucial function in the induction of acquired immune responses, dendritic cells have also recently been found to be involved in innate immunity by their capacity to recognize potent pathogens and to generate protective cytokine responses (6).
Although macrophages have classically been described as the prime target of mycobacterial infection, more recent experiments performed in mice indicate that dendritic cells also become infected by BCG in vivo and may constitute an important reservoir for the long-term survival of the mycobacteria (7). The same report also demonstrated that dendritic cells, not macrophages, are the major leukocyte subset involved in triggering the immune response to mycobacterial infection. Therefore, the fact that dendritic cells are present not only at the pathogen's sites of entry but also in the granuloma, where they continue to sample mycobacterial antigens, is of significant importance for our understanding of tuberculosis latency and reactivation. The findings of Tsuchiya and coworkers indicate that the granuloma allows the immune system to continuously sense and control the mycobacteria during latent infection. Their discovery also raises hopes that the dormant mycobacteria might be susceptible to immunotherapy against latent tuberculosis. It would now be of great interest to explore which subsets of dendritic cells are activated in the granulomas (CD8 Two notes of caution need to be introduced. First, a limitation of the present study is that heat-killed, not live, bacteria were used, which may elicit the proliferation of distinct T cell subsets from those triggered by live bacteria (11). Second, there are important differences between rodents, such as mice and rats, and humans with regard to granuloma formation and host defense against tuberculosis. In the mouse model, lymphocytes are not confined to the mantle of the mycobacterial granuloma but infiltrate well into its center. This may reflect a fundamental difference in the way T cells are activated in these animals (12). In granulomas induced in guinea pigs and rabbits, however, large numbers of epithelioid macrophages are present, surrounded by a mantle of lymphocytes and monocytes much like the granulomas seen in human tuberculosis. Regardless, neither of these animal models can reproduce tuberculosis latency well. Therefore, we are anxious to see the exciting results from the animal model confirmed in studies of granulomas from human tissues. In conclusion, granuloma formation plays a prime role in the host's defense against chronic infection. The work of Tsuchiya and colleagues provides new evidence that the function of granulomas in mycobacterial infection goes far beyond the simple confinement of the pathogens behind a cell wall. Their findings underline the dynamic nature of the immunologic (hypersensitive type) granuloma that is induced by chronic infection, in contrast to the nonimmunologic granuloma that is the host response to (nonmicrobial) foreign bodies. The conclusion to be drawn from the study of Tsuchiya and coworkers is that granulomas function to constantly revive acquired and innate immunity against the persisting microbes. Why these immune responses seldom lead to the total eradication of M. tuberculosis in the human host remains to be elucidated. However, there is hope that these new insights into the immunologic role of the granuloma may have implications for the design of better mycobacterial vaccines or for novel immunotherapeutic responses to tuberculosis. REFERENCES
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