Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming.

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity. [Display omitted] • KCs are required for in vivo reinvigoration of intrahepatically primed T cells by IL-2 • KCs respond to IL-2 and cross-present hepatocellular Ags • Single-cell RNA-seq identifies two distinct populations of KCs • KC2s have enriched IL-2 sensing machinery and Ag presentation capacity De Simone et al. delineate the mechanisms by which hepatocellularly primed HBV-specific CD8+ T cells acquire antiviral effector functions following IL-2 administration. These mechanisms rely on KCs and, in particular, on a hitherto unidentified KC subset, referred to as KC2, that is poised to respond to IL-2 and cross-present viral antigens. [ABSTRACT FROM AUTHOR]