BCG Skin Infection Triggers IL-1R-MyD88-Dependent Migration of EpCAMlow CD11bhigh Skin Dendritic cells to Draining Lymph Node During CD4+ T-Cell Priming.

Vishnu Priya Bollampalli,Hans Blom,Yu Gao,Damiën Bierschenk,Xiaogang Feng,Susanne Nylén,Lívia Harumi Yamashiro,Antonio Gigliotti Rothfuchs,Birgitta Henriques-Normark,Padmini Salgame

doi:10.1371/journal.ppat.1005206

Abstract

The transport of antigen from the periphery to the draining lymph node (DLN) is critical for T-cell priming but remains poorly studied during infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG). To address this we employed a mouse model to track the traffic of Dendritic cells (DCs) and mycobacteria from the BCG inoculation site in the skin to the DLN. Detection of BCG in the DLN was concomitant with the priming of antigen-specific CD4+ T cells at that site. We found EpCAMlow CD11bhigh migratory skin DCs to be mobilized during the transport of BCG to the DLN. Migratory skin DCs distributed to the T-cell area of the LN, co-localized with BCG and were found in close apposition to antigen-specific CD4+ T cells. Consequently, blockade of skin DC traffic into DLN dramatically reduced mycobacterial entry into DLN and muted T-cell priming. Interestingly, DC and mycobacterial entry into the DLN was dependent on IL-1R-I, MyD88, TNFR-I and IL-12p40. In addition, we found using DC adoptive transfers that the requirement for MyD88 in BCG-triggered migration was not restricted to the migrating DC itself and that hematopoietic expression of MyD88 was needed in part for full-fledged migration. Our observations thus identify a population of DCs that contribute towards the priming of CD4+ T cells to BCG infection by transporting bacilli into the DLN in an IL-1R-MyD88-dependent manner and reveal both DC-intrinsic and -extrinsic requirements for MyD88 in DC migration.

Highlights

Lymph nodes (LNs) make use of lymphatic drainage and a specialized microanatomy to facilitate productive encounters between antigen-laden Dendritic cells (DCs) and naïve T cells [1]
The arrival of bacilli in the lymph node is a bottleneck for initiating T cell responses to mycobacteria but remains poorly studied
To begin dissecting the early events following Bacille Calmette-Guérin (BCG) infection, we established a model where C57BL/6 mice are inoculated with BCG in the footpad skin and immune responses assessed in the draining LN (DLN)

Summary

Introduction

Lymph nodes (LNs) make use of lymphatic drainage and a specialized microanatomy to facilitate productive encounters between antigen-laden Dendritic cells (DCs) and naïve T cells [1]. Microbial triggering of PRRs unleashes an intracellular signaling cascade in DCs that culminates in enhanced antigen presentation, up-regulation of co-stimulatory molecules and cytokine production. This activation process enables DCs upon engaging a naïve T cell clone to direct the expansion and differentiation of that clone into an armed, effector T-cell population [3]. Mounting a robust immune response mediated by Th1 effector cells is an important outcome for successful tuberculosis vaccination In this context, cutaneous infection with the attenuated strain of M. bovis called Bacille Calmette-Guérin (BCG) is the only vaccination available against M. tuberculosis, but is lacking in clinical efficacy. The channeling of antigen from the BCG-inoculation site in the skin to the draining LN (DLN) remains poorly studied

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