Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation

Abstract

In contrast to other solid organ transplantations, liver grafts have tolerogenic properties. Animal models indicate that donor leukocytes transferred into the recipient after liver transplantation (LTX) play a relevant role in this tolerogenic phenomenon. However, the specific donor cell types involved in modulation of the recipient alloresponse are not yet defined. We hypothesized that this unique property of liver grafts may be related to their high content of organ-specific natural killer (NK) and CD56 þ T cells. Here, we show that a high proportion of hepatic NK cells that detach from human liver grafts during pretransplant perfusion belong to the CD56bright subset, and are in an activated state (CD69 þ ). Liver NK cells contained perforin and granzymes, exerted stronger cytotoxicity against K562 target cells when compared with blood NK cells, and secreted interferon-c, but no interleukin-10 or T helper 2 cytokines, upon stimulation with monokines. Interestingly, whereas the CD56bright subset is classically considered as noncytolytic, liver CD56bright NK cells showed a high content of cytolytic molecules and degranulated in response to K562 cells. After LTX, but not after renal transplantation, significant numbers of donor CD56dim NK and CD56 þ T cells were detected in the recipient circulation for approximately 2 weeks. In conclusion, during clinical LTX, activated and highly cytotoxic NK cells of donor origin are transferred into the recipient, and a subset of them mixes with the recirculating recipient NK cell pool. The unique properties of the transferred hepatic NK cells may enable them to play a role in regulating the immunological response of the recipient against the graft and therefore contribute to liver tolerogenicity. Liver Transpl 16:895-908, 2010. V C 2010 AASLD.Received December 23, 2009; accepted March 28, 2010. It is generally recognized that after clinical liver transplantation (LTX), the incidence of chronic rejection is lower than after transplantation of other organ grafts. Furthermore, in about 20% of LTX recipients, immunosuppressive therapy can be withdrawn without occurrence of graft rejection.1 Various animal models are spontaneously tolerant to LTX, even though they reject other organs.2,3 Furthermore, cotransplantation of a liver allograft can prevent rejection of other organ grafts from the same donor. 4,5 The mechanisms responsible for this relative tolerogenicity of the liver have only been partially elucidated. A number of observations in animal models indicate that the immune cells present in the liver graft may play a relevant role in the induction of tolerance. With LTX, so-called passenger leukocytes from the donor are transferred into the recipient and can establish a condition of chimerism of variable proportions and duration.6,7 Independent studies from different groups have shown that in rat models,

Defining Early Human NK Cell Developmental Stages in Primary and Secondary Lymphoid Tissues

“…bright NK cells in the liver itself show a more immature phenotype as compared to their counterpart in PB [31]. The differences in NK cell differentiation in situ after NK cell commitment may be due to the regional immune system of the liver, which is characterized by relatively weak cellular immune responses and hyporesponsiveness to antigens and bacterial product derived from the intestines [32].…”

Tissue-resident natural killer cells in the livers

“…In humans, liver NK cells with equal proportions of CD56 bright and CD56 dim subsets can account up to 30%-40% of total hepatic lymphocytes (Moroso et al, 2010), in contrast to their low frequency in other tissues. Previous studies about human liver NK cells have been mainly focused on their roles in liver diseases including viral infections, fibrosis, and tumors (Araujo et al, 2014;Fasbender et al, 2016;Rehermann, 2013); however, few studies have specifically descripted the characteristics of human liver NK cells under homeostatic conditions.…”

Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance?

“…NK cells constitute the largest proportion of lymphoid cells in the human liver, comprising 30-50% of hepatic lymphocytes (6,10,11). Over 45% of the hepatic NK cells are CD56…”