title: Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen.
abstract: The chronic presence of viral Ags can induce T cell exhaustion, which is characterized by upregulation of coinhibitory receptors and loss of T cell function. We studied whether a similar phenomenon occurs after liver transplantation (LTx), when there is continuous exposure to alloantigen. Expression of coinhibitory receptors on circulating CD4(+) and CD8(+) T cells was analyzed longitudinally in 19 patients until 6 mo after LTx and cross-sectionally in 38 patients late (1-12 y) after LTx. Expression of the coinhibitory receptors CD160 and CD244 on circulating CD8(+) T cells was already higher 6 mo after LTx compared with pre-LTx, and the elevated expression was sustained late after LTx, with CD244 showing the more prominent increase. The strongest upregulation of CD244 on circulating CD8(+) T cells was observed in patients who experienced CMV infection after LTx. CMV infection also was associated with reduced CD8(+) T cell proliferation and cytotoxic degranulation in response to alloantigen late after LTx. Purified CD244(+)CD8(+) T cells from LTx patients showed lower proliferative responses to alloantigen, as well as to polyclonal stimulation, than did their CD244(-) counterparts. In addition, the CD244(+)CD8(+) T cell population contained the majority of CMV peptide-loaded MHC class I tetramer-binding cells. In conclusion, CMV infection after LTx, rather than persistence of alloantigen, induces the accumulation of dysfunctional CD244(+)CD8(+) T cells in the circulation that persist long-term, resulting in reduced frequencies of circulating alloreactive CD8(+) T cells. These results suggest that CMV infection restrains CD8(+) T cell alloresponses after LTx.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Emmy L D
authors.initials: EL
authors.lastname: de Mare-Bredemeijer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Xiao-lei
authors.initials: XL
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Rogier
authors.initials: R
authors.lastname: van Gent
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Marieke
authors.initials: M
authors.lastname: van der Heide-Mulder
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; and.
authors.forename: Renate
authors.initials: R
authors.lastname: de Boer
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; and.
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands;
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015 CE, the Netherlands; j.kwekkeboom@erasmusmc.nl.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D016031:Liver Transplantation / Q000009:adverse effects; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000235:genetics*; D000071176:Signaling Lymphocytic Activation Molecule Family; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C114505:CD160 protein, human; C084093:CD244 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family