Research Highlights

Abstract

Longevity and Replenishment of Human Liver-resident Memory T Cells and Mononuclear Phagocytes Pallett LJ, Burton AR, Amin OE, et al. J Exp Med. 2020;217(9):e20200050. There is an increasing interest in tissue resident leukocytes and their role in mediating rejection and tissue regeneration after transplantation.1 However, not a great deal is known about graft-resident populations in the liver after transplantation.2 Pallett et al3 investigated the composition of liver-resident immune cells in HLA-mismatched donor–recipient pairs after transplantation. They found that the majority of cells were recipient-derived cells recruited from the periphery but that a donor-derived population persisted in the graft, even up to 10 years after transplantation. Interestingly, this appeared to be unique to the liver, as no such chimerism was detected in the peripheral blood. Additionally, certain populations including polymorphonuclear cells, NK, T, and NKT cells persisted more effectively than other cell types, such as dendritic cells. The infiltrating cells acquired tissue-resident and liver-resident features and even replicated the ratios of cell types normally found in the liver, such as the higher CD8:CD4 ratio that is normally found in the periphery. This suggests that the liver microenvironment can recruit cells and alter their phenotype to fit liver-resident requirements, regardless of HLA provenance. The infiltrating cells acquired phenotypic markers including the expression of Kupffer/macrophage cell marker CD68 but still were distinguishable from embryonically seeded donor cells in the expression of a few markers, such as HMOX1, CD206, and CD163, indicating that the phenotype induced is not identical to native tissue-resident cells. This phenotypic malleability has implications in cellular therapy, if the graft is capable of controlling which cell types it recruits and is capable of then morphing their phenotype according to its homeostatic composition. The presence of a long-lived donor-derived resident population is also of interest for localized chimerism within the graft, which may help facilitate tolerance.4 This is particularly relevant as donor T cells persisted, but dendritic cells did not. Whether this long-lived chimerism is restricted to the liver or can be achieved in other organs is a matter of great relevance for adoptive cellular therapies. Sympathetic Nervous Tone Limits the Development of Myeloid-derived Suppressor Cells Nevin JT, Moussa M, Corwin WL, et al. Sci Immunol. 2020;5(51):eaay9368. The immune system can respond to a huge variety of physiological cues. Sympathetic nervous system (SNS) release of norepinephrine directly signals to various immune cells via adrenergic receptors (ARs) expressed on their surface, known to modify their function.1 In the study from Nevin et al,2 the authors investigated the impact of ablation of SNS signaling on myeloid cells in mice. Sympathetic signaling was targeted using neurotoxin 6-hydroxydopamine, which is selectively taken up by sympathetic terminals and results in their degradation. Sympathectomized mice had increased polymorphonuclear (PMN) and monocytic cell populations with phenotypes consistent with polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and mononuclear MDSCs (M-MDSCs). They found that the CD11b+ compartment from sympathectomized mice was more suppressive than that of control mice, specifically the CD11b+Ly6CintLy6G+ PMN-MDSC subpopulation. Single-cell RNA sequencing revealed a shift in the PMN population in SNS-ablated mice, with an enrichment of immature cells and a decrease in cells expressing the mature neutrophil marker CD101, as well as an increase in proliferation. Sympathectomized mice also had an increase in regulatory T cell (Treg) populations in a Gr1-dependent manner. The mechanism behind this was further elucidated with the use of α-AR and ß-AR agonists and antagonists, which revealed that ß-AR agonism and α-AR antagonism both reproduced the effects of SNS ablation and induced MDSC proliferation and impaired maturity. As α-ARs have higher affinity for norepinephrine than ß-ARs, the researchers suggest that tonal SNS signaling preferentially affects α-ARs and that SNS ablation therefore reduces this to induce MDSC development. Additionally, they suggest that s100a8-s100a9 heterodimers secreted by MDSCs may be responsible for the observed Treg induction, as this heterodimer has been shown to signal via CD69 to induce STAT5 phosphorylation. Indeed, iTreg induced in the presence of s100a8-s100a9 heterodimers showed increased Foxp3 expression and proliferation even in the absence of IL-2, suggesting that this dimer can compensate via alternative STAT5 phosphorylation. Naturally suppressive cell populations such as Tregs and MDSCs are of significant interest to the field of transplantation for their ability to therapeutically control alloresponses.3,4 Understanding the various physiological changes that modify leukocyte behavior after transplantation is critical. This study sheds some light on the physiological mechanisms that control these leukocyte populations and has implications for transplantation where transplanted organs are denervated or the settings of organ failure and surgery in which there is autonomic system activation.