The Adaptor Molecule MyD88 Directly Promotes CD8 T Cell Responses to Vaccinia Virus

Abstract

Vaccinia virus (VACV) elicits a robust CD8 T cell response that plays an important role in host resistance. To date, there is little information on the molecules that are essential to generate large pools of VACV-specific effector CD8 T cells. In this study, we show that the adaptor molecule MyD88 is critical for the magnitude of primary CD8 T cell responses to both dominant and subdominant VACV epitopes. MyD88−/− mice exhibit profound reduction in CD8 T cell expansion and antiviral cytokine production. Surprisingly, the defect was not due to impaired APC function, as MyD88−/− dendritic cells matured normally and were able to promote strong CD8 T cell priming following VACV infection. Rather, adoptive transfer experiments demonstrated that intrinsic MyD88-dependent pathways in CD8 T cells were critical. MyD88-deficient CD8 T cells failed to accumulate in wild-type hosts and poor expansion of MyD88-deficient VACV-specific CD8 T cells resulted after virus infection. In contrast, no defect was evident in the absence of TRIF, TLR2, TLR4, TLR9, and IL-1R. Together, our results highlight an important role for MyD88 in initial antiviral CD8 T cell responses and suggest that targeting this pathway may be useful in promoting and sustaining anti-VACV immunity.

Boosting Functional Avidity of CD8 + T Cells by Vaccinia Virus Vaccination Depends on Intrinsic T-Cell MyD88 Expression but Not the Inflammatory Milieu

“…6C). In agreement with previous reports (20,21,35), these data demonstrate that the inflammatory cytokines induced by VACV infection are decreased and that the ability to induce a CD8 ϩ T-cell response is retained in MyD88…”

The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice

“…with 2 × 10 5 PFU VACV. Effector responses were analyzed between days 7 and 8 after infection, while memory responses were analyzed 30 or more days after infection, after restimulating in vitro with VACV peptides as described previously (52). For dermal scarification, virus (10 μl) was deposited at the base of the tail, and the skin at the site of the droplet was scarified 25-30 times with a 25-gauge needle.…”

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

“…TRAF6 is an E3 ubiquitin ligase and catalyzes K63 polyubiquitination of TAK1, which is required for IKK activation and is known to directly regulate ubiquitination and activation of AKT and mTORC1 as well as TGF-β (14)(15)(16)(17). Interestingly, CD4 or CD8 T cells lacking MyD88 exhibit reduced expansion and impaired survival in vivo (4)(5)(6)(7)(8)(9)(10). IRAK4 has been reported to be recruited to T cell lipid rafts, where it associates with ZAP70 and participates in protein kinase C activation (18).…”

“…Recent studies highlight an indispensable role for MyD88 signaling in primary T cells (4)(5)(6)(7)(8)(9)(10). The engagement of IL-1 receptor family members as well as TLRs (except TLR3) recruits the adapter protein MyD88, which in turn brings in an IL-1 receptor-associated kinase 4 (IRAK4), resulting in autophosphorylation.…”