Pallett et al. identify tissue-resident memory CD8 T cells compartmentalized in the healthy human liver that expand in controlled hepatotropic infection and can swiftly produce antiviral cytokines. This prototype may inform the development of liver-targeted T cell immunotherapy.

Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p < 0.0001). Human hepatic CXCR6+ NK had an immature phenotype (predominantly CD56brightCD16−CD57−), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6− fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bethiEomeslo(CXCR6−) and T-betloEomeshi(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bethiEomeslo, suggesting its lineage was closer to CXCR6− peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-betloEomeshi NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible anti-viral immunity.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.Correspondence should be addressed to M.C. (carringm@mail.nih.gov). Note: Supplementary information is available on the Nature Genetics website. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. AUTHOR CONTRIBUTIONS NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 December 1. Recently, however, a scan for genetic variants that influence the control of viral load indicated that a dimorphism 35 kb upstream of the HLA-C gene (-35C/T) had one of the two strongest genome-wide effects on the level of plasma viremia in early, established HIV infection as measured by viral load set-point, although no significant association of this variant was observed with progression to a CD4 cell count of <350 (ref.2 ). Notably, the -35C variant that associates with low viral load has also been shown to associate with high HLA-C mRNA levels in a codominant manner among a group of individuals of European ancestry 12,13 , although whether it associates with cell surface expression has not been tested. These findings suggest that certain HLA-C allotypes might have a primary role in restricting HIV replication through innate and/or acquired immune mechanisms that have previously been overlooked. Here we present data from 1,698 European American individuals, indicating that high levels of HLA-C confer strong protection early in the course of HIV infection and this early protection of high HLA-C extends to some extent into chronic infection. We propose a model in which highexpression HLA-C alleles might confer better innate and/or acquired immune responses than low-expression HLA-C alleles. RESULTS Effect of-35 on mean viral loadThe effect of -35 genotypes on mean plasma HIV load (mVL) measurements was tested in a group of 935 seroincident European American individuals (see Online Methods). Each individual was categorized into one of three groups based on their mVL (<2,000, 2,000-10,000 and >10,000 mean viral RNA copies per ml plasma), and the frequency of ea...

Human liver contains an Eomeshi population of NK cells that is not present in the blood. In this study, we show that these cells are characterized by a molecular signature that mediates their retention in the liver. By examining liver transplants where donors and recipients are HLA mismatched, we distinguish between donor liver–derived and recipient-derived leukocytes to show that Eomeslo NK cells circulate freely whereas Eomeshi NK cells are unable to leave the liver. Furthermore, Eomeshi NK cells are retained in the liver for up to 13 y. Therefore, Eomeshi NK cells are long-lived liver-resident cells. We go on to show that Eomeshi NK cells can be recruited from the circulation during adult life and that circulating Eomeslo NK cells are able to upregulate Eomes and molecules mediating liver retention under cytokine conditions similar to those in the liver. This suggests that circulating NK cells are a precursor of their liver-resident counterparts.