Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes

Abstract

The human liver contains specialized subsets of mononuclear phagocytes (MNPs) and T cells, but whether these have definitive features of tissue residence (long-term retention, lack of egress) and/or can be replenished from the circulation remains unclear. Here we addressed these questions using HLA-mismatched liver allografts to discriminate the liver-resident (donor) from the infiltrating (recipient) immune composition. Allografts were rapidly infiltrated by recipient leukocytes, which recapitulated the liver myeloid and lymphoid composition, and underwent partial reprogramming with acquisition of CD68/CD206 on MNPs and CD69/CD103 on T cells. The small residual pool of donor cells persisting in allografts for over a decade contained CX3CR1hi/CD163hi/CD206hi Kupffer cells (KCs) and CXCR3hi tissue-resident memory T cells (TRM). CD8+ TRM were found in the local lymph nodes but were not detected egressing into the hepatic vein. Our findings inform organ transplantation and hepatic immunotherapy, revealing remarkably long-lived populations of KCs and TRM in human liver, which can be additionally supplemented by their circulating counterparts.

Resident Memory T Cells and Their Role within the Liver

“…As mentioned earlier, contrary to liver T RM cells in mice which express high levels of Hobit and low to intermediate levels of Blimp1 [73], human liver T RM cells are Hobit low Blimp1 high [58]. In a recent publication, a small proportion of donor cells were found in HLA-mismatched liver and allografts 11 years after transplant, demonstrating the resident nature and remarkable longevity of these cells [104].…”

Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists

“…The CD69+CD103− subpopulation is proposed to be a subpopulation that can recirculate and take on other functions upon pathogen challenge, whereas the CD69+CD103+ are defined to be truly liver resident [ 9 ]. In contrast, it could be shown that the majority of CD4+ T RM cells are long living and tissue-resident cells that express high levels of CD69 and show a low CD103 expression [ 10 ].…”

“…Additionally, they showed that recipient CD8+ and CD4+ T cells could develop a T RM phenotype although the recipient-derived T RM cells tended to express fewer liver-resident markers. Furthermore, a small population of donor-derived CD4+ T RM cells was detectable [ 10 ]. To conclude, there are strong indications that liver T RM cells can develop from two different origins ( Figure 2 ).…”

“…A very recent study from Pallett et al was able to investigate HLA-mismatched liver transplant patients, allowing to discriminate liver-resident (donor) from newly infiltrating (recipient) T cells. Allogenic liver tissues were rapidly infiltrated by recipient T cells that underwent reprogramming to express the T RM markers CD69, CD103 and CXCR3 hi , which is important for intrahepatic retention [ 10 ]. Interestingly, long-lived liver-resident donor T RM cells could even be detected after more than a decade (2–6% of intrahepatic CD8+ T cells) and it was found that they do not egress into the recipient circulation via the hepatic vein.…”

“…By analyzing an allograft of a donor with HBV infection, it could be demonstrated that donor-derived, virus-specific T RM cells persist for a very long time. In addition, the recipient also develops virus-specific T RM cells that were detectable within the donor-derived liver tissue and interestingly also in the blood, albeit in a lower quantity [ 10 ]. In HBV-related HCC, CD8+ T RM cell enrichment could be correlated to an improved prognosis [ 84 ].…”