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

作者：Heidi A. Schreiber, Paul D. Hulseberg, Jangeun Lee, J. Prechl, P. Barta, Nóra Szlávik, J. Harding, Z. Fabry, M. Sandor · 发表于：PLoS ONE · 年份：2010 · DOI：10.1371/journal.pone.0011453 · 被引用次数：54 · 研究领域：Biology、Medicine

Background Mycobacterium-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 Findings We 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/Significance Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acti...