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

Abstract

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.

Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection

“…The lack of a significant correlation may be a result of the small sample size studied here. Furthermore, protection may be mediated primarily by nonrecirculating liver-resident T cells that cannot be directly measured in the blood (14,35).…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…119 Murine liver T RM cells are identified as CD69 + CXCR6 + CXCR3 + CD11a + CD103 − . 120,121 In contrast to most T RM cells that are located outside the vasculature, the vast majority of liver T RM cells reside inside the blood vessels and display active crawling behavior to patrol hepatic sinusoids. 108,120–122 This unique feature excludes the usage of intravascular labeling technique in liver T RM research.…”

“…120,121 In contrast to most T RM cells that are located outside the vasculature, the vast majority of liver T RM cells reside inside the blood vessels and display active crawling behavior to patrol hepatic sinusoids. 108,120–122 This unique feature excludes the usage of intravascular labeling technique in liver T RM research. Even constantly exposed to blood circulation, liver T RM are not travelling along the bloodstream and considered as bona fide liver-resident cells as demonstrated by parabiosis experiments.…”

“…Their liver residency is dependent on integrin LFA-1 (Lymphocyte Function-associated Antigen-1) and chemokine receptor CXCR3. 120,121 Local antigen is required for liver T RM formation. At the transcription level, both Blimp-1 and Hobit are required for the maintenance of liver T RM in mouse.…”

Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory

“…Indeed, we lack in vivo data for mucosal T RM cell motility, which is intrinsically related to the scanning rate of potential target cells. Intravascular T RM cells that patrol liver sinusoids are motile, but it is unclear whether this is true of the numerous T RM cells that survey connective tissues and parenchymal barriers 13 . Indeed, T RM cell motility in skin epidermis is quite low (~2 μm min −1 ), in contrast to that of T CM cells surveilling LNs (~10 μm min −1 ) 15,17–19 .…”