Showing papers by "David Voehringer published in 2010"
TL;DR: It is demonstrated that basophils play an important role for protective immunity against helminths and orchestrate chronic allergic inflammation, whereas primary Th2 cell responses can operate efficiently in the absence of this cell type.
319 citations
TL;DR: The authors' data document an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4+ T cell tolerance and support an avidity model of Treg cell development versus deletion.
Abstract: Medullary thymic epithelial cells (mTECs) serve an essential function in central tolerance by expressing peripheral-tissue antigens. These antigens may be transferred to and presented by dendritic cells (DCs). Therefore, it is unclear whether mTECs, in addition to being an antigen reservoir, also serve a mandatory function as antigen-presenting cells. Here we diminished major histocompatibility complex (MHC) class II on mTECs through transgenic expression of a 'designer' microRNA specific for the MHC class II transactivator CIITA (called 'C2TA' here). This resulted in an enlarged polyclonal CD4(+) single-positive compartment and, among thymocytes specific for model antigens expressed in mTECs, enhanced selection of regulatory T cells (T(reg) cells) at the expense of deletion. Our data document an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4(+) T cell tolerance and support an avidity model of T(reg) cell development versus deletion.
237 citations
TL;DR: In vivo blockade of PD-L2 during N brasiliensis infection caused an enhanced Th2 response in the lung, indicating that AAM inhibit Th2 cells by expression of PD -L2.
179 citations
TL;DR: It is concluded that basophils play a crucial role for worm expulsion during a memory type 2 immune response independently of mast cells and memory Th2 cells.
Abstract: Hookworms infect several hundred million people worldwide, causing malnutrition, anemia, and growth retardation. Infections generally result in a strong type 2 immune response, but the effector mechanisms that mediate worm expulsion remain poorly characterized. In this study, we determined the role of mast cells and basophils in protective immunity against the murine hookworm, Nippostrongylus Brasiliensis , during primary and secondary infection. Mast cell–deficient c-Kit W-sh mice had lower serum IgE levels compared with wild-type mice under steady-state conditions and after N. brasiliensis infection. Worm expulsion was delayed during primary but not during secondary infection of c-Kit W-sh mice, even in the absence of CD4 T cells. However, protective immunity was lost when basophils were depleted before reinfection of c-Kit W-sh mice. We conclude that basophils play a crucial role for worm expulsion during a memory type 2 immune response independently of mast cells and memory Th2 cells.
103 citations
TL;DR: KLRG1 is a marker for distinct NK and T‐cell differentiation stages but it does not play a deterministic role in the generation and functional characteristics of these lymphocyte subsets and activation signals during viral infections may override the inhibitory signal in vivo.
Abstract: The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK and T-cell subsets and recognizes members of the classical cadherin family. KLRG1 is widely used as a lymphocyte differentiation marker in both humans and mice but the physiological role of KLRG1 in vivo is still unclear. Here, we generated KLRG1-deficient mice by homologous recombination and used several infection models for their characterization. The results revealed that KLRG1 deficiency did not affect development and function of NK cells examined under various conditions. KLRG1 was also dispensable for normal CD8+ T-cell differentiation and function after viral infections. Thus, KLRG1 is a marker for distinct NK and T-cell differentiation stages but it does not play a deterministic role in the generation and functional characteristics of these lymphocyte subsets. In addition, we demonstrate that E-cadherin expressed by K562 target cells inhibited NK-cell reactivity in transgenic mice over-expressing KLRG1 but not in KLRG1-deficient or WT mice. Hence, the inhibitory potential of KLRG1 in mice is rather weak and strong activation signals during viral infections may override the inhibitory signal in vivo.
64 citations
TL;DR: Use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination is described and the linkage between cell tropism and immunogenicity is allowed.
Abstract: Human cytomegalovirus (HCMV) is a human pathogen that causes severe disease primarily in the immunocompromised or immunologically immature individual. To date, no vaccine is available. We describe use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination. To generate a spread-deficient MCMV, the conserved, essential gene M94 was deleted. Immunization with MCMV-DeltaM94 is apathogenic and protective against wild-type challenge even in highly susceptible IFNalphabetaR(-/-) mice. MCMV-DeltaM94 was able to induce a robust CD4(+) and CD8(+) T-cell response as well as a neutralizing antibody response comparable to that induced by wild-type infection. Endothelial cells were identified as activators of CD8(+) T cells in vivo. Thus, the vaccination with a spread-deficient betaherpesvirus is a safe and protective strategy and allows the linkage between cell tropism and immunogenicity. Furthermore, genomes of MCMV-DeltaM94 were present in lungs 12 months after infection, revealing first-target cells as sites of genome maintenance.
53 citations
TL;DR: It is demonstrated that intranasal administration of OVA and chitin resulted in diminished T‐cell expansion and Th2 polarization as compared with OVA administration alone.
Abstract: Chitin is a highly abundant glycopolymer, which serves as structural component in fungi, arthropods and crustaceans but is not synthesized by vertebrates. However, vertebrates express chitinases and chitinase-like proteins, some of which are induced by infection with helminths suggesting that chitinous structures may be targets of the immune system. The chitin-induced modulations of the innate and adaptive immune responses are not well understood. Here, we demonstrate that intranasal administration of OVA and chitin resulted in diminished T-cell expansion and Th2 polarization as compared with OVA administration alone. Chitin did not promote nor attenuate Th2 polarization in vitro. Chitin-exposed macrophages inhibited proliferation of CD4+ T cells in a cell–cell contact-dependent manner. Chitin induced upregulation of the inhibitory ligand B7-H1 (PD-L1) on macrophages independently of MyD88, TRIF, TLR2, TLR3, TLR4 and Stat6. Inhibition of T-cell proliferation was largely dependent on B7-H1, as the effect was not observed in cocultures with cells from B7-H1-deficient mice.
22 citations