title: Early intrahepatic antigen-specific retention of naïve CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice.
abstract: We have previously shown that naïve CD8+ T cells recognizing their cognate antigen within the liver are retained and undergo activation in situ, independent from lymphoid tissues. Intrahepatic primary T cell activation results in apoptosis and may play a crucial role in the ability of the liver to induce tolerance. Although adhesion molecules required for intrahepatic retention of T cells that have undergone previous extra-hepatic activation have been characterized, adhesive interactions involved in selective antigen-dependent intrahepatic retention of naïve CD8+ T cells have not been investigated. By adoptively transferring radiolabeled T cell receptor (TCR)-transgenic CD8+ T cells into recipient animals ubiquitously expressing the relevant antigen, we show that 40% to 60 % of donor antigen-specific naïve CD8+ T cells were retained in the liver within 1 hour after transfer, despite ubiquitous expression of the antigen. Intravital microscopy showed that most donor naïve T cells slowed down and were irreversibly retained intrahepatically within the first few minutes after adoptive transfer, strongly suggesting that they were directly activated by liver cells in situ. This process was largely dependent on LFA-1 and ICAM-1, but was independent of blocking with antibodies against VCAM-1, alpha4 integrin, P-selectin, VAP-1, and beta1 integrin. ICAM-2 seemed to play only a minor role in this process. Interestingly, LFA-1 expressed by both donor T cells and liver cells was involved in retention of the antigen-reactive T cells. In conclusion, LFA-1-dependent intrahepatic T cell retention and activation are linked events that may play a crucial role in the establishment of liver-induced antigen-specific tolerance.
authors.affiliation: AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Newtown, NSW, Australia. p.bertolino@centenary.usyd.edu.au
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
authors.forename: Arnhild
authors.initials: A
authors.lastname: Schrage
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.forename: Katja
authors.initials: K
authors.lastname: Klugewitz
authors.forename: Saeed
authors.initials: S
authors.lastname: Ghani
authors.forename: Katharina
authors.initials: K
authors.lastname: Eulenburg
authors.forename: Lauren
authors.initials: L
authors.lastname: Holz
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D000906:Antibodies; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1