Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1β, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNα, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.

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Galectin-3 belongs to a family of ␤-galactoside-bind-proposed that Th2 cells play a key pathogenic role in AD, which is supported by the presence of peripheral blood eosinophilia and enhanced serum IgE levels in a majority of AD patients. In acute lesions of AD, there is a significant increase in the number of cells expressing IL-4, IL-5, and IL-13 mRNA and proteins, suggesting preferential accumulation of Th2 cells. Our current understanding of AD is that there is a predominant Th2 cytokine milieu in the initiating stages or acute lesions of AD and a mixed Th1 and Th2 pattern in chronic lesions.

We evaluated gamma-irradiated Listeria monocytogenes as a killed bacterial vaccine, testing the hypothesis that irradiation preserves antigenic and adjuvant structures destroyed by traditional heat or chemical inactivation. Irradiated Listeria monocytogenes (LM), unlike heat-killed LM, efficiently activated dendritic cells via Toll-like receptors and induced protective T cell responses in mice. Like live LM, irradiated LM induced Toll-like-receptor-independent T cell priming. Cross-presentation of irradiated listerial antigens to CD8(+) T cells involved TAP- and proteasome-dependent cytosolic antigen processing. These results establish that killed LM can induce protective T cell responses, previously thought to require live infection. gamma-irradiation may be potentially applied to numerous bacterial vaccine candidates, and irradiated bacteria could serve as a vaccine platform for recombinant antigens derived from other pathogens, allergens, or tumors.

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Dendritic cells play a critical role in the initiation and maintenance of inflammatory responses. Galectin-3, a protein found in DCs, is a carbohydrate-binding protein implicated in several cellular processes. In mouse models of asthma and atopic dermatitis, galectin-3-deficient (gal3-/-) mice had significantly fewer infiltrating eosinophils and displayed lower Th2 but higher Th1 responses compared to wild-type mice, suggesting that galectin-3 plays a key role in allergic inflammation. Given the ability of DCs to direct the T lymphocyte response, we hypothesized that galectin-3 may affect immune responses by altering DC functions and tested the hypothesis by comparing wild-type and gal3-/- DCs. OT-II CD4+ cells cultured with OVA-pulsed gal3-/- DCs generated higher Th1 responses relative to gal3+/+ DCs, and the differences were diminished following IL-12 neutralization. Moreover, gal3-/- DCs expressed more IL-12p35 mRNA than gal3+/+ DCs, indicating that gal3 may modulate IL-12 at the transcriptional level or through upstream signaling pathways. T cells co-cultured with gal3-/- DCs also secreted more IL-17 than cells cultured with gal3+/+ DCs, suggesting that gal3 may also negatively regulate Th17 responses. Furthermore, we observed higher IL-6 secretion and IL-23p19 expression in gal3-/- DCs, which may contribute to the enhanced Th17 polarization induced by these cells. We conclude that gal3 may regulate DC cytokine expression, thereby modulating T helper responses.

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