Dendritic Cells in Chronic Mycobacterial Granulomas Restrict Local Anti-Bacterial T Cell Response in a Murine Model

Abstract

BackgroundMycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood.Methodology/Principal FindingsWe report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c+ cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c+ cells from acute granulomas. As a consequence of their phenotype, CD11c+ cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85B-specific CD4+IFNγ+ T cells or induce an IFNγ response from naïve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c+ cells from chronic lesions to stimulate a protective IFNγ T cell response.Conclusions/SignificanceOur data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explain why mycobacteria are adapted for long-term survival in granulomatous lesions.

Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor

“…Indeed, mycobacterial infection induces a delicate equilibrium between proinflammatory and anti-inflammatory immune responses, and this is well illustrated in pulmonary granulomas where mycobacteria can reside for decades. Although macrophages are the cells mostly involved in the control of mycobacteria, DCs are also an additional reservoir for BCG (8) or M. tuberculosis (10) and, when infected, display an impaired ability to present Ag to T cells (8,9). Infected DCs and macrophages need to cooperate with other cells not only to control the infection, but also to regulate the host immune response.…”

“…We believe that BCG is an acceptable model for interactions taking place between DCs, neutrophils, and CD4 T cells in the lung with fully virulent M. tuberculosis for the following reasons: 1) the important role of IL-17 in granuloma formation has been first shown in BCG infected mice (19) and later confirmed with M. tuberculosis (18); 2) production of IL-10 by infected neutrophils in vitro and in vivo has been demonstrated both after BCG and M. tuberculosis infection (38); 3) in vivo DC infection has been shown both with BCG (8,9,54) and M. tuberculosis (55,56); and 4) recruitment of neutrophils to the site of infection has been shown both with BCG (13,57) and M. tuberculosis (58,59). We propose a model (Fig.…”

“…The host cells allowing mycobacterial persistence are mostly macrophages. We (8) and others (9,10) have established that DCs are also reservoirs for persistent mycobacteria. Infected DCs can migrate out of the chronic mycobacterial granulomas and disseminate the infection among the lymphoid organs (11).…”

Control of Chronic Mycobacterium tuberculosis Infection by CD4 KLRG1− IL-2–Secreting Central Memory Cells

“…For CD4 T cells, the phenomenon is not nearly as well characterized and understood, but there are clear indications that immune regulation and functional exhaustion take place in a number of chronic infections (18)(19)(20)(21)(22). In animal models, ongoing TB infection has recently been reported to drive T cells into a stage of terminal differentiation (23).…”

“…In mice models, we have previously reported that adoptive transfer of M. tuberculosis-specific memory cells (from cleared infection or after subunit vaccination) can confer significant protection to challenge (30,31), and that central memory T cells (T CM ) are the most important subset responsible for this effect (30). Immune regulation exerted by inhibitory receptor signaling such as KLRG1, through the PD-1-PD-L1/2 axis, regulatory T cells, and immunosuppressive cytokines, are all mechanisms developed to avoid excess immunopathology (32); but in TB, there is increasing evidence that these pathways also play an important role in the longterm maintenance of the equilibrium needed to support chronic infection (20,21). Thus, to be successful, any novel vaccine strategy to boost BCG needs to be able to overcome or counteract all these complex signals in an environment of chronic TB infection and maintain a reservoir of specific self-renewing T cells that can mediate long-term containment.…”