Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers

Liver-resident CD8+ T cells: Learning lessons from the local experts

“…10 In this issue of Journal of Hepatology, Kim et al accessed large number of perfusates from living liver donors to investigate the heterogeneity within the CD8+ T RM compartment to further unpick their roles in immunity and pathology. 11 Their data suggest that a subset of those liver CD8+ T cells that are capable of contributing to bystander liver damage can be regulated by hypoxia-inducible factor (HIF)-2a.…”

“…The human liver houses sizeable populations of both CD69+CD103-and CD69+CD103+ CD8+ T cells, that can be separated from infiltrating, but non-resident, CD69-CD103-T cells by their expression of several features common to resident memory T cells (S1PR1 hi , CXCR6, CD49a and a lack of KLF2 expression). [1][2][3]6,11 Kim et al specifically highlight the numerical dominance of the CD69+CD103-T RM -like population, that express chemokine receptors supporting liver retention (CXCR6, CXCR3, and a lack of CX 3 CR1 1,3,6,11 ) but exhibit an intermediate phenotype between the non-resident, tissue-infiltrating CD69-CD103and CD69+CD103+ T RM . Prolonged exposure to environmental cues may be needed for a CD69+CD103-T RM -like cell to differentiate into a double positive CD69+CD103+ T RM ; cytokines, such as TGFb and IL-33, are known inducers of CD103 expression.…”

“…6,13 TCR engagement by cognate antigen recognition within the tissue may also drive CD103 expression: 6,14 in support of this, Kim et al find more CD103 expression on intrahepatic T cells specific for hepatotropic compared to non-hepatotropic viral infections. 11 The CD69+CD103-T RM -like population described by Kim et al are enriched for terminally differentiated memory T cells expressing CD45RA (T EMRA ; CD45RA re-expression, CCR7-), which are also readily identified in the blood, and expand with age and cytomegalovirus (CMV) seropositivity. 15 Despite their name, T EMRA are far from inert or fully senescent T cells as they have the ability to mediate pathogen clearance and/or tissue damage via innate-like cytotoxic pathways, such as NKG2D.…”

“…14 Interestingly, Kim et al show that CD69+CD103-T RM -like cells responded to stimulation with the prototypical liver cytokine IL-15 by upregulating NKG2D, which also conferred on them innate-like cytolytic function, in line with the authors' recent study. 10,11 Whilst IL-15-driven expansion of heterologous CD8+ T cell responses may contribute to protection in acute viral infections, 16 in situations of chronic inflammation it can represent a tissue-specific danger signal, that promotes damage through licensing of bystander T cells and NK cells. 17 The highly abundant CD69+CD103-T RM -like population could, therefore, represent a pool of T cells lodged within the local microenvironment with the potential to mediate cytotoxic bystander tissue damage.…”

“…Using pharmacological or genetic knockdown of HIF2a, Kim et al show that this transcription factor is required by CD69+CD103-T cells for survival and optimal functionality upon bystander or TCR-stimulation. 11 Although HIF1a expression has been linked to T cell differentiation and metabolic reprogramming, 20 the role of HIF2a has not been studied in detailed. CD69+CD103-T cells were the dominant population in livers with acute hepatitis A infection or cirrhosis, and their expression of HIF2a was further increased in disease.…”