Mycobacterium bovis BCG decreases MHC-II expression in vivo on murine lung macrophages and dendritic cells during aerosol infection

Abstract

Mycobacterium tuberculosis and M. bovis BCG infect APCs. In vitro, mycobacteria inhibit IFNgamma-induced MHC-II expression by macrophages, but the effects of mycobacteria on lung APCs in vivo remain unclear. To assess MHC-II expression on APCs infected in vivo, mice were aerosolinfected with GFP-expressing BCG. At 28 d, ~1% of lung APCs were GFP+ by flow cytometry and CFU data. Most GFP+ cells were CD11b high /CD11c neg-mid lung macrophages (58-68%) or CD11b high /CD11c high DCs (28-31%). Lung APC MHC-II expression was higher in infected mice than naïve mice. Within infected lungs, however, MHC-II expression was lower in GFP+ cells than GFP− cells for both macrophages and DCs. MHC-II expression was also inhibited on purified lung macrophages and DCs that were infected with BCG in vitro. Thus, lung APCs that harbor mycobacteria in vivo have decreased MHC-II expression relative to uninfected APCs from the same lung, possibly contributing to evasion of T cell responses.

Pulmonary Mycobacterial Granuloma

“…Specifically, many tumors as well rely on the induction of IL-10 and other immune suppressive cytokines to dampen type 1 immune responses and to remain immune evasive. 65 In a fashion similar to that of the tumor, although it is believed that mycobacteria may simultaneously use multiple mechanisms of immune evasion including mechanisms of down-regulating antigen presentation, 42,61 in the current study we have shown that IL-10 is one of the essential mechanisms through which the immune suppressive environment of mycobacterial granuloma is maintained. Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others.…”

“…To address the major cellular sources displaying such type 1 immune suppression, we first analyzed the major APC populations by using purified CD11cϩ and CD11bϩ cells, which are most likely dendritic cells and macrophages, respectively. 28,42 Our data show that these CD11cϩCD11bϩ/Ϫ and CD11c-/ CD11bϩ APCs are the most prominent APC populations in both the airway lumen and granuloma (Table 1). These cells were shown to be a significant cellular source of TNF-␣, IFN-␥, IL-10, and NO in various models of pulmonary mycobacterial infection.…”

“…11,12,42,52 Furthermore, the critical role of type 1 T-cell immunity, including the role of CD4 T cells and type 1 cytokines in antimycobacterial host defense, has shown to be true for pulmonary infection elicited by exposure to either BCG or M.tb. 11,12,[53][54][55][56][57] M. bovis BCG also uss similar immune evasion strategies as M.tb to dampen host immune activation mechanisms including intracellular persistence, 58 -60 inhibiting MHC molecule expression, 42,61 and inducing IL-10 production. [37][38][39]62 Despite these described similarities, we must caution that, compared with Immunosuppression of Bacterial Granuloma 1631 AJP April 2011, Vol.…”

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

“…Although it was initially thought that alveolar macrophages represented the major target of infection by mycobacteria, recent findings have also identified DCs as a cellular target of mycobacterial infection [3,21]. DCs have long been identified to be a major cell type involved in the delivery and presentation of antigen to naive T cells [8,29] and as such represent a critical linkage between the innate and adaptive immune responses.…”

“…It has been well established that the initiation of adaptive immunity is critically dependent on the activation of early innate immune responses. There is abundant in vitro evidence to suggest that infection by slow-growing mycobacterial species inhibits the activation of innate macrophages and DCs [21][22][23][24]. However, whether early innate immune activation is impaired in vivo following pulmonary mycobacterial infection and how this activation relates to delayed Th1-type immunity is still poorly understood.…”