The uptake, transport, and presentation of Ags by lung dendritic cells (DCs) are central to the initiation of CD8 T cell responses against respiratory viruses. Although several studies have demonstrated a critical role of CD11blow/negCD103+ DCs for the initiation of cytotoxic T cell responses against the influenza virus, the underlying mechanisms for its potent ability to prime CD8 T cells remain poorly understood. Using a novel approach of fluorescent lipophilic dye-labeled influenza virus, we demonstrate that CD11blow/negCD103+ DCs are the dominant lung DC population transporting influenza virus to the posterior mediastinal lymph node as early as 20 h postinfection. By contrast, CD11bhighCD103neg DCs, although more efficient for taking up the virus within the lung, migrate poorly to the lymph node and remain in the lung to produce proinflammatory cytokines instead. CD11blow/negCD103+ DCs efficiently load viral peptide onto MHC class I complexes and therefore uniquely possess the capacity to potently induce proliferation of naive CD8 T cells. In addition, the peptide transporters TAP1 and TAP2 are constitutively expressed at higher levels in CD11blow/negCD103+ DCs, providing, to our knowledge, the first evidence of a distinct regulation of the Ag-processing pathway in these cells. Collectively, these results show that CD11blow/negCD103+ DCs are functionally specialized for the transport of Ag from the lung to the lymph node and also for efficient processing and presentation of viral Ags to CD8 T cells.

Foxp3(+) CD4(+) regulatory T cells (Tregs) represent a highly suppressive T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, although the role of these cells in acute viral infections is poorly understood. The present study sought to examine the induction of Foxp3(+) CD4(+) Tregs in a nonlethal murine model of pulmonary viral infection by the use of the prototypical respiratory virus influenza A. We establish that influenza A virus infection results in a robust Foxp3(+) CD4(+) T cell response and that regulatory T cell induction at the site of inflammation precedes the effector T cell response. Induced Foxp3(+) CD4(+) T cells are highly suppressive ex vivo, demonstrating that influenza virus-induced Foxp3(+) CD4(+) T cells are phenotypically regulatory. Influenza A virus-induced regulatory T cells proliferate vigorously in response to influenza virus antigen, are disseminated throughout the site of infection and primary and secondary lymphoid organs, and retain Foxp3 expression in vitro, suggesting that acute viral infection is capable of inducing a foreign-antigen-specific Treg response. The ability of influenza virus-induced regulatory T cells to suppress antigen-specific CD4(+) and CD8(+) T cell proliferation and cytokine production correlates closely to their ability to respond to influenza virus antigens, suggesting that virus-induced Tregs are capable of attenuating effector responses in an antigen-dependent manner. Collectively, these data demonstrate that primary acute viral infection is capable of inducing a robust, antigen-responsive, and suppressive regulatory T cell response.

CD8a + DC are implicated as the principle DC subset for cross-presentation and crosspriming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8a + DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8a + DC, but not CD8a -DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-c and CD40L, which is rapidly up-regulated poststimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8a + DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. Key words: CD8 T cells Á Dendritic cells Á IL-12p70Introduction DC are essential for the activation and polarization of T cells during an adaptive immune response [1,2]. DC respond to stimulatory signals from microbes and inflammatory mediators and mature into professional antigen-presenting cells that prime the adaptive immune system [3,4]. DC activity is also influenced through direct and indirect interaction with other effector immune cells, which results in the delivery of "feedback" signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response [5][6][7]. CD8 T cells are principally known for their role in cytotoxic killing. However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12]. CD8 T cells can have a direct impact on DC during their interaction, inducing DC to mature [13], and enhancing their Th1-polarizing capabilities by augmenting their ability to produce 14,15].IL-12p70 is a heterodimeric pro-inflammatory cytokine that plays a central role in Th1 immunity, acting on T cells and NK cells by inducing proliferation, cytotoxic function and IFN-c production [16]. IL-12p70 production by DC during T cell priming is crucial for the development of Th1 responses [16][17][18]. Hence, control of DC IL-12p70 production is important for the development of Th1 immunity.Previous reports on CD8 T cell-mediated IL-12p70 production utilized DC generated from monocytes or bone marrow progenitors using 14,15]. These DC are now thought to appear only under inflammatory conditions [19]. They differ markedly from DC that reside in lymphoid organs, and hence do not necessarily reflect events that occur with lymphoid resident DC. Splenic DC comprise of a heterogeneous population of cells with different phenotypes and functional characteristics [20]. It is unknown whether CD8 T cells could possibly modulate IL-12p70 production with splenic resident DC, or whether CD8 T cellme...

Protective memory CD8 T cell responses are generally associated with the rapid and efficient acquisition of CTL function. However, the ability of memory CD8 T cells to modulate immune responses through interactions with dendritic cells (DCs) during the early states of secondary Ag exposure is poorly understood. In this study, we show that murine Ag-specific CD44high CD8 T cells, representing CD8 T cells of the memory phenotype, potently activate DCs to produce high levels of IL-12p70 in conjunction with stimulation of DCs with the TLR 9 ligand, unmethylated CpG DNA. IL-12p70 production was produced predominantly by CD8α+ DCs and plasmacytoid DCs, and mediated by CD8 T cell-derived cytokines IFN-γ, GM-CSF, TNF-α, and surface CD40L. We also find that CD44high memory phenotype CD8 T cells were better DC IL-12p70 stimulators than CD44low naive phenotype CD8 T cells, and this was attributed to higher levels of IFN-γ and GM-CSF produced by CD44high memory phenotype CD8 T cells during their Ag specific interaction with DCs. Our study identifies CpG DNA as the most effective TLR ligand that cooperates with CD8 T cells for DC IL-12p70 production, and suggests that effectiveness of memory CD8 T cells could be attributed to their ability to rapidly and effectively induce protective Th1 immunity during early stages of pathogen reinfection.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by broad clinical manifestations including cardiovascular and renal complications with periodic disease flares and significant morbidity and mortality. One of the main contributing factors to the pathology of SLE is the accumulation and impaired clearance of immune complexes of which the principle components are host auto-antigens and antibodies. The contribution of host lipids to the formation of these autoimmune complexes remains poorly defined. The aim of the present study was to identify and analyze candidate lipid autoantigens and their corresponding anti–lipid antibody responses in a well-defined SLE patient cohort using a combination of immunological and biophysical techniques. Disease monitoring in the SLE cohort was undertaken with serial British Isles Lupus Assessment Group (BILAG) scoring. Correlations between specific lipid/anti-lipid responses were investigated as disease activity developed from active flares to quiescent during a follow up period. We report a significant negative correlation between anti-lipid antibodies for 24S-hydroxycholesterol, cardiolipin and phosphatidylserine with SLE disease activity. Taken together, these data suggest that lipid autoantigens represent a new family of biomarkers that can be employed to monitor disease activity plus the efficacy of therapeutic intervention in SLE.

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