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Differential ability of surface and endosomal TLRs to induce CD8 T cell responses in vivo.

ABSTRACT: TLR activation on dendritic cells (DCs) induces DC maturation and secretion of proinflammatory cytokines, both of which are important for activation and differentiation of CD4 T cells. The importance of TLR activation on DCs for CD8 T cell responses is less clear. In this study, we tested the ability of different TLRs to regulate CD8 T cell responses to pathogens. We found that although all TLRs are able to induce CD8 T cell activation in vitro, there are profound differences in their ability to activate CD8 T cells in vivo. The nucleic acid recognizing endosomal TLRs, TLR3 and TLR9, had a potent ability to induce CD8 T cell activation. However, the surface TLRs, TLR2 and TLR4, that recognize bacterial ligands were not only incapable of inducing CD8 T cell priming, but they had a dominant effect of inhibiting CD8 T cell expansion induced by activation of endosomal TLRs. We found that TLR2 and TLR4, acting in a MyD88-dependent manner, influenced CD8 T cell priming by altering the composition of DCs in the draining lymph nodes. Our results have important implications for combined bacterial and viral infections and suggest that bacterial infections could constrain the ability of the host to mount effective antiviral CD8 T cell immunity.

SUBMITTER: Mandraju R

PROVIDER: S-EPMC4002505 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Differential ability of surface and endosomal TLRs to induce CD8 T cell responses in vivo.

Mandraju Rajakumar R Murray Sean S Forman James J Pasare Chandrashekhar C

Journal of immunology (Baltimore, Md. : 1950) 20140331 9

TLR activation on dendritic cells (DCs) induces DC maturation and secretion of proinflammatory cytokines, both of which are important for activation and differentiation of CD4 T cells. The importance of TLR activation on DCs for CD8 T cell responses is less clear. In this study, we tested the ability of different TLRs to regulate CD8 T cell responses to pathogens. We found that although all TLRs are able to induce CD8 T cell activation in vitro, there are profound differences in their ability to ...[more]

PMID: 24688022

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Project description:A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8(+) T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8(+) T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i.p. immunization, is required for the subsequent activation of cross-presenting lymphoid organ-resident CD8α(+) DCs. In contrast, s.c. or i.m. immunization usually results in the formation of a depot at the site of injection (SOI), which hinders the self-drainage and targeting of the vaccine to cross-presenting CD8α(+) DCs. We investigated this hypothesis by correlating the biodistribution pattern and the adjuvanticity of the strong CD8(+) T-cell inducing liposomal cationic adjuvant formulation 09 (CAF09), which is composed of dimethyldioctadecylammonium bromide/monomycoloyl glycerol liposomes with polyinosinic:polycytidylic acid electrostatically adsorbed to the surface. Biodistribution studies with radiolabeled CAF09 and a surface-adsorbed model antigen [ovalbumin (OVA)] showed that a significantly larger fraction of the vaccine dose localized in the draining lymph nodes (dLNs) and the spleen 6h after i.p. immunization, as compared to after i.m. immunization. Studies with fluorescently labelled OVA+CAF09 demonstrated a preferential association of OVA+CAF09 to DCs/monocytes, as compared to macrophages and B cells, following i.p. immunization. Administration of OVA+CAF09 via the i.p. route did also result in DC activation, whereas no DC activation could be measured within the same period with unadjuvanted OVA and OVA+CAF09 administered via the s.c. or i.m. routes. In the dLNs, the highest level of activated, cross-presenting CD8α(+) DCs was detected at 24h post immunization, whereas an influx of activated, migrating and cross-presenting CD103(+) DCs to the dLNs could be measured after 48h. This suggests that the CD8α(+) DCs are activated by self-draining OVA+CAF09 in the lymphoid organs, whereas the CD103(+) DCs are stimulated by the OVA+CAF09 at the SOI. These results support the hypothesis that the self-drainage of OVA+CAF09 to the draining LNs is required for the activation of CD8α(+) DCs, while the migratory CD103(+) DCs may play a role in sustaining the subsequent induction of strong CD8(+) T-cell responses.

Dataset Information

Differential ability of surface and endosomal TLRs to induce CD8 T cell responses in vivo.

Publications

Differential ability of surface and endosomal TLRs to induce CD8 T cell responses in vivo.

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