+ 2 CD8 DC, but Not CD8 DC, Isolated from BCG-Infected Mice Reduces Pathological Reactions Induced by Mycobacterial Challenge Infection Xiaoling Gao1, Shuhe Wang 1 , Yijun Fan1, Hong Bai1,2, Jie Yang 1 , Xi Yang1,2* 1 Laboratory for Infection and Immunity, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, 2 Department of Immunology, Tianjin Medical University, Tianjin, People’s Republic of China Abstract Background: Tuberculosis is a mycobacterial infection causing worldwide public health problems but the available vaccine is far from ideal. Type-1 T cell immunity has been shown to be critical for host defence against tuberculosis infection, but the role of dendritic cell (DC) subsets in pathogenesis of mycobacterial infection remains unclear. Methodology/Principal Findings: We examined the effectiveness of dendritic cell (DC) subsets in BCG-infected mice in generating immune responses beneficial for pathogen clearance and reduction of pathological reactions in the tissues following challenge infection. Our data showed that only the adoptive transfer of the subset of CD8a+ DC isolated from infected mice (iCD8+ DC) generated significant protection, demonstrated by less mycobacterial growth and pathological changes in the lung and liver tissues in iCD8+ DC recipients than sham-treated control mice. The adoptive transfer of the CD8a2DC from the infected mice (iCD82 DC) not only failed to reduce bacterial growth, but enhanced inflammation characterized by diffuse heavy cellular infiltration. Notably, iCD82 DC produced significantly higher levels of IL-10 than iCD8+ DC and promoted more Th2 cytokine responses in in vitro DC-T cell co-culture and in vivo adoptive transfer experiments. Conclusions/Significance: The data indicate that in vivo BCG-primed CD8+ DC is the dominant DC subset in inducing protective immunity especially for reducing pathological reactions in infected tissues. The finding has implications for the rational improvement of the prophylactic and therapeutic approaches for controlling tuberculosis infection and related diseases. Citation: Gao X, Wang S, Fan Y, Bai H, Yang J, et al. (2010) CD8+ DC, but Not CD82DC, Isolated from BCG-Infected Mice Reduces Pathological Reactions Induced by Mycobacterial Challenge Infection. PLoS ONE 5(2): e9281. doi:10.1371/journal.pone.0009281 Editor: Anil Kumar Tyagi, University of Delhi, India Received October 30, 2009; Accepted January 29, 2010; Published February 18, 2010 Copyright: 2010 Gao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to X.Y. (MT16480). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: yangxi@cc.umanitoba.ca Introduction Tuberculosis is a type of mycobacterial infection that causes serious public health problems worldwide. The World Health Organization (WHO) estimates that about 2 billion people, meaning one third of the world’s population, are infected with Mycobacterium tuberculosis (Mtb) [1,2]. More importantly, the incidence of tuberculosis continues to rise due to the spread of HIV infection and the emergence of multi-drug-resistant Mtb strains [3,4]. Mtb infection is the leading cause of death in AID patients. BCG (Bacille Calmette -Gue´rin) is the only registered human vaccine for prevention of Mtb infection and diseases. Although its protective effect has been well established, its efficacy is quite variable and far from ideal [5]. A better understanding of the mechanism by which BCG immunization protects host from challenge infection may be not only useful for the possible improvement of the efficacy of this particular vaccine but also have implications in the rational development of new vaccines for tuberculosis. Although the mechanism remains unclear, the host protection against Mtb infection has been found to be largely dependent on T cell mediated immunity especially type-1 T cell responses. The influence of type-2 T cells and humoral immune responses to host defence is limited and even detrimental in certain circumstances. Human studies have shown that Th1 response is essential for the host protection from mycobacterial infections [6]. The human subjects deficient in receptors for IFN-c and IL-12 are profoundly susceptible to mycobacterial infections [7,8]. Experimental studies using animal models also confirmed the critical importance of Th1 responses in protective immunity and the control of pathological reactions (reviewed in [8,9]. T cell response is a downstream event in the immune system, following the capture, process and presentation of antigenic peptides by antigen-presenting cells (APC). Along with macro- phages and others, dendritic cells (DCs) are a type of the front line cells that encounter Mycobacteria in the infection sites. DCs are the key APCs in the activation of primary CD4 T cells and in the polarization of Th1/Th2 subsets. It has been shown that Mtb- infected DCs, but not macrophages, can drive na¨ıve CD4+ T cells polarize to Th1 pathway [10]. The DCs in the lung play a central role in initiating the immune response to tuberculosis [11]. DCs can influence the polarization of naive T cell to different types of effector T cells [12,13]. Since DC is a heterogeneous population, different DC subtypes may contribute differently on the activation and polarization of mycobacterial antigen-specific T cells. Indeed, PLoS ONE | www.plosone.org 1 February 2010 | Volume 5 | Issue 2 | e9281