Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.
BACKGROUND
The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic.


OBJECTIVE
We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NK) cells from circulating counterparts.


RESULTS
Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56(bright) lr-NK cells that localize within hepatic sinusoids. CD56(bright) lr-NK cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. Here, we also show that hepatic sinusoids express CCL3(pos) Kupffer cells, CXCL16(pos) endothelial cells and CCL5(pos) T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56(bright) NK cells that constitutively express CCR5 and CXCR6. CD56(bright) lr-NK cells co-exist with CD56(dim) conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56(dim) c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3CR1.


CONCLUSIONS
Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56(bright) lr-NK cells will require modification of hepatic CCR5 and CXCR6.
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
Kelly
K
Hudspeth
Department of Hepatobiliary & General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Matteo
M
Donadon
Department of Hepatobiliary & General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Matteo
M
Cimino
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
Elena
E
Pontarini
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
Paolo
P
Tentorio
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
Max
M
Preti
Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science; Technology and Research (A*STAR), 169587, Singapore.
Michelle
M
Hong
Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science; Technology and Research (A*STAR), 169587, Singapore.
Antonio
A
Bertoletti
Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, 41100 Modena, Italy.
Silvio
S
Bicciato
Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, 20089 Rozzano, Italy; Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, USA.
Pietro
P
Invernizzi
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
Enrico
E
Lugli
Department of Hepatobiliary & General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Guido
G
Torzilli
Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, USA. Electronic address: megershwin@ucdavis.edu.
M Eric
ME
Gershwin
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20089 Rozzano, Italy. Electronic address: domenico.mavilio@unimi.it.
Domenico
D
Mavilio
D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism*; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D037181:Lectins, C-Type; D019713:Receptors, CCR5; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D017452:Receptors, IgG; D011991:Receptors, Virus; D000099192:CD69 Antigens; C584933:CCR5 protein, human; C106330:CXCR6 protein, human
Cherokees Chemokine receptors; Homing of hepatic NK cells; Liver immunology