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.
Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes. Transfer of highly polarized transgenic CD4 effector Th2 cells, termed BT-II, followed by repeated inhalation of Blo t 5 expands these cells in the lung >100-fold, and subsequent Blo t 5 challenge induced decreased body temperature, reduction in movement, and a fall in specific lung compliance unseen in conventional mouse asthma models following a physiological allergen challenge. These mice exhibit lung eosinophilia; smooth muscle cell, collagen, and goblet cell hyperplasia; hyper IgE syndrome; mucus plugging; and extensive inducible BALT. In addition, there is a fall in total lung volume and forced expiratory volume at 100 ms. These pathophysiological changes were substantially reduced and, in some cases, completely abolished by administration of neutralizing mAbs specific for IL-4 and IL-13 on weeks 1, 2, and 3. This IL-4/IL-13-dependent inducible BALT model will be useful for investigating the pathophysiological mechanisms that underlie asthma and the development of more effective drugs for treating severe asthma.
CD8 T cells play an important role in protective immunity against a wide range of pathogens and the factors that control their activation are clearly important. CD40L-mediated CD40 licensing of dendritic cells by CD4 T cells is known to be necessary for the generation of a robust CD8 T cell response. Less clear is the contribution of CD40L on CD8 T cells to their activation. We have previously shown that CD8 T cells are able to induce the production of IL-12 p70 by dendritic cells in a CD40L-dependent manner. To better understand the role of CD40L on CD8 T cells responses, we generated and characterized CD40L-expressing CD8 T cells both in vitro and in vivo. We found that CD40L is expressed on 30-50% of activated effector CD8 T cells and the differentiation of CD8 T cells into CD40L-expressing cells is strongly induced by IL-12, suggesting the presence of a positive feedback mechanism mediated by CD40L and IL-12. Using an influenza A mouse model, we examined whether this mechanism is involved in the primary expansion of CD8 T cells during an infection and whether CD40L-expressing CD8 T cells are able to license dendritic cells for optimal memory CD8 T cell programming. In the absence of CD40L signaling, the ability to upregulate CD25 and downregulate CD62L is diminished in CD8 T cells, causing an impairment in their primary expansion and also their ability to accumulate at the site of infection.
Patients with severe asthma are very difficult to manage are present a major medical challenge. Development of clinical asthma requires many years of patient exposure to allergens. Mouse asthma models require weeks and are normally transitory and do not lead to allergen-induced dyspnea. We have followed an alternative approach to conventional immunization through the transfer highly polarized CD4 T cell receptor transgenic T cells specific for the dust mite allergen Blo t 5 followed by thrice weekly intranasal recombinant challenge with recombinant allergen to induce persistent high levels of eosinophilia (4 million/mouse lavage) and serum IgE (40,000 ng/ml) and specific IgG1 (30,000 ng/ml). Intranasal challenge of these mice with 25ug of allergen is well tolerated, but a fourfold increase to 100ug induces respiratory symptoms within 15 minutes. These mice show evidence of mucus plugging, increased collagen deposition, mucus hypersecretion and the formation of bronchial associated lymphoid structures (iBALT). Neutralization of IL-4 or IL-13 with monoclonal antibody reduced the response and a combination of these two was most effective. Many drugs reduce respiratory inflammation in mice yet fail to benefit asthmatic patients. We hope that the model described here may help identify new/better drugs for the treatment of patients with severe asthma.
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