Liver-Resident Memory CD8⁺ T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection

Highlights

• CD8⁺ tissue-resident memory T cells (Trm cells) can be found in the murine liver

• These liver Trm cells survey the liver from within the sinusoids

• A prime-and-trap vaccination strategy efficiently induces liver Trm cells

• Liver Trm cells are essential for protection against liver-stage malaria after vaccination

Summary

In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8⁺ T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.