LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8⁺T cells

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

“…A caveat to this experiment is that the defect we observed with IRF3 2/2 BMDC may be caused by insufficient activation of the BMDC with LPS prior to transfer. However, in terms of LTbR 2/2 BMDC, we had previously shown that they can produce normal levels of IFN-I and IL-12 in response to LPS stimulation, and they express comparable level of costimulatory molecules such as CD80/CD86 and MHC-II upon activation (20). Hence, the defect observed in the LTbRdeficient scenario is likely at the level of CD8 + T cell priming rather than a poor response to TLR4 stimulation.…”

“…Because LTbR signaling can facilitate IFN-I expression in DCs (20) and IFN-I is particularly important for the programming of CTLs (4, 5, 31, 32), we queried whether adoptive transfer of LCMV-GP peptide-loaded BMDC that are incapable of producing IFN-I would have a similar effect in RIP-GP mice compared with RIP-GP mice that received LCMV-GP peptidepulsed LTbR 2/2 BMDC. Accordingly, we transferred BMDC generated from IFN regulatory factor 3 (IRF3)-deficient mice into the RIP-GP host to assess their capacity to induce disease.…”

“…We previously showed that LTbR signaling in DC is essential for CD8 + T cells to fully expand in response to a nonreplicating protein Ag, OVA (20). To assess whether CD8 + T cell expansion in response to an endogenous autoantigen is likewise dependent on DC-intrinsic LTbR signaling, we examined the frequency of LCMV-GP-specific CD8 + T cells in recipient mice post-BMDC transfer (note that for mice that did not receive LCMV-GP peptideloaded DC, LCMV-GP-specific CD8 + T cells were not detectable by tetramer analysis and therefore not shown).…”

“…Signaling through TLR-3, -4, -7, and -9 as well as the RIG-I-like receptors can induce rapid and robust IFN-I production in response to infection (2). Interestingly, recent studies have hinted that the TNFR superfamily (TNFRSF) members, TNFR-1, TNFR-2, receptor activator for NF-kB (RANK), and lymphotoxin (LT)-b receptor (LTbR), are also capable of inducing IFN-I production; however, in contrast to PRR activation, TNFRSF members typically elicit a very modest, albeit sustained level of IFN-I production (19)(20)(21)(22)(23).…”

“…+ T cells provides a help signal through the LTbR on DC, and this LTbR-dependent T cell:DC cross talk was required to optimize CD8 + T cell expansion in vitro and in vivo in response to protein Ag (20). Although the induction of IFN-I via PRR signaling has been well characterized (24), the relevance and mechanism of TNFRSF-facilitated IFN-I, specifically in the context of an autoimmune attack on a self-tissue, are not well understood.…”