Abstract
We previously reported that Tim-3, an immune checkpoint inhibitor, inhibits MHC-II expression, but the molecular mechanisms involved and the implications for antiviral immunity remain to be determined. Here, we found that during H1N1 infection, Tim-3 inhibits MHC-II expression in macrophages/microglia in vitro. Tim-3 interacts with MHC-II via its intracellular tail and induces proteasomal dependent degradation of MHC-II. In H1N1 infected macrophages/microglia, Tim-3 promotes the K48-linked ubiquitination of MHC-II via MARCH8, a ubiquitin E3 ligase that can be upregulated by Tim-3. In H1N1 infected mice, specific knockout of Tim-3 in macrophages leads to a decreased viral load, attenuates tissue damage and increases the survival rate. We have thus identified a novel mechanism by which Tim-3 mediates virus immune escape. Manipulating the Tim-3-MHC-II signaling pathway may provide a novel treatment for viral infections.
Published Version
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