IL-12 Is Required to Maintain a Th1 Response During Leishmania major Infection

The kinetics of CD8 T cell IFN-γ responses as they occur in situ are defined here during lymphocytic choriomeningitis virus (LCMV) infections, and a unique mechanism for the innate cytokines IFN-αβ and IL-18 in promoting these responses is defined. Infections of mice with Armstrong or WE strains of LCMV induced an unexpectedly early day 4 IFN-γ response detectable in serum samples and spleen and liver homogenates. Production of IFN-γ was MHC class I/CD8 dependent, but did not require IL-12, NK cells, TCR-γδ T cells, MHC class II, or CD4 T cells. Peak response required specific Ag recognition, as administration of antagonist peptide partially impaired day 4 IFN-γ induction, and viral peptide stimulation enhanced CD8 T cell IFN-γ expression in culture. The IFN-γ response was associated with IL-18 and IFN-αβ expression. Furthermore, both factors augmented peptide-driven IFN-γ production in culture, and mice lacking IL-18 or IFN-αβ functions had reduced day 4 IFN-γ. Collectively, these results demonstrate that during viral infections, there is a dramatic in vivo CD8 T cell response preceding maximal expansion of these cells, and that the mechanism supporting this response is dependent on endogenous innate cytokines. Because stimulation by microbial products is linked to innate cytokine expression, the studies also suggest a pathway for precisely limiting T cell functions to times of need.

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections

Pien

Nguyen

Malmgaard

et al. 2002

“…In WT mice, this protocol results in a disease closely mimicking the cardinal features of severe asthma in humans, including pulmonary eosinophil inflammation, high circulating levels of IgE, and a predominance of CD4 T cell-derived IL-4 and IL-5 (29,31). Based on previous reports that have documented the role of TLR4 signaling in the production of IL-12 in response to LPS (7), the importance of IL-12 in Th1 cell generation and maintenance in many in vivo contexts (35)(36)(37)(38), and the potential inhibitory "cross-regulation" by Th1 cells or IL-12 on Th2 differentiation to unrelated Ags (39, 40), we predicted that mice lacking TLR4 signaling would display a more severe asthmatic phenotype compared with WT mice. Surprisingly, allergen-induced inflammation of the airway, particularly with eosinophils, and plasma IgE levels were both substantially decreased in mice with defective TLR4 signaling compared with WT controls of the same genetic background.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells

Dabbagh

Dahl

Stepick-Biek

et al. 2002

206

127

LPS potently induces dendritic cell maturation and the production of proinflammatory cytokines, such as IL-12, by activation of Toll-like receptor 4 (TLR4). Since IL-12 is important for the generation and maintenance of Th1 responses and may also inhibit Th2 cell generation from naive CD4 T cell precursors, it has been inferred that TLR4 signaling would have similar effects via the induction of IL-12 secretion. Surprisingly, we found that TLR4-defective mice subjected to sensitization and pulmonary challenge with a protein allergen had reductions in airway inflammation with eosinophils, allergen-specific IgE levels, and Th2 cytokine production, compared with wild-type mice. These reduced responses were attributable, at least in part, to decreased dendritic cell function: Dendritic cells from TLR4-defective mice expressed lower levels of CD86, a costimulatory molecule important for Th2 responses. They also induced less Th2 cytokine production by antigenically naive CD4 T cells in vitro and mediated diminished CD4 T cell Ag-specific pulmonary inflammation in vivo. These results indicate that TLR4 is required for optimal Th2 responses to Ags from nonpathogenic sources and suggest a role for TLR4 ligands, such as LPS derived from commensal bacteria or endogenously derived ligands, in maturation of the innate immune system before pathogen exposure.

“…Cells (4 ϫ 10 6 /ml) were plated in 24-or 96-well plates (1 ml or 200 l, respectively) in complete tissue culture medium (DMEM supplemented with 10% FBS, 5 ϫ 10 Ϫ5 M 2-ME, 2 mM L-glutamine, 100 U/ml penicillin, and 100 g/ml streptomycin) and stimulated with 50 g/ml SLA as previously described (21). Cells were incubated at 37 o C for 72 h and supernatants were assayed for cytokines by ELISA as previously described (21).…”

Section: Cytokine Productionmentioning

confidence: 99%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

Self Cite

119

118

Long-term immunity to Leishmania may require the continued presence of parasites, but previous attempts to create attenuated parasites that persist without causing disease have had limited success. Since Leishmania major mutants that lack lipophosphoglycan and other secreted phosphoglycans, termed lpg2−, persist indefinitely in infected mice without inducing any disease, we tested their ability to provide protection to virulent L. major challenge. In response to leishmanial Ag stimulation, cells from lpg2−-infected mice produced minimal levels of IL-4 and IL-10, as well as very low levels of IFN-γ. Nevertheless, when BALB/c mice infected with lpg2− parasites were challenged with virulent L. major they were protected from disease. Thus, these findings report on attenuated parasites that may be used to induce long-term protection against leishmaniasis and indicate that the immunity induced can be maintained in the absence of a strong Th1 response.