The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses

Abstract

The liver remains a hematopoietic organ after birth and can produce all leukocyte lineages from resident hematopoietic stem cells. Hepatocytes produce acute phase proteins and complement in bacterial infections. Liver Kupffer cells are activated by various bacterial stimuli, including bacterial lipopolysaccharide (LPS) and bacterial superantigens, and produce interleukin (IL)-12. IL-12 and other monokines (IL- 18 etc.) produced by Kupffer cells activate liver natural killer (NK) cells and NK1.1 Ag+ T cells to produce interferon-gamma and thereby acquire cytotoxicity against tumors and microbe-infected cells. These liver leukocytes and the T helper 1 immune responses induced by them thus play a crucial role in the first line of defense against bacterial infections and hematogenous tumor metastases. However, if this defense system is inadequately activated, shock associated with multiple organ failure takes place. Activated liver NK1.1 Ag+ T cells and NK cells also cause hepatocyte injury. NK1.1 Ag+ T cells and another T-cell subset with an intermediate T-cell receptor, CD 122+CD8+ T cells, can develop independently of thymic epithelial cells. Liver NK cells and NK1.1 Ag+ T cells physiologically develop in situ from their precursors, presumably due to bacterial antigens brought from the intestine via the portal vein. NK cells activated by bacterial superantigens or LPS are also probably involved in the vascular endothelial injury in Kawasaki disease.

Anthrax Lethal Toxin Kills Macrophages in a Strain-Specific Manner by Apoptosis or Caspase-1-Mediated Necrosis

“…Kupffer cells are bone marrow-derived specialized macrophages in the liver. 44 Sections of BALB/c liver collected at 16, 24, and 48 hours post-LT injection were devoid of Kupffer cells, while the six-hour sections appeared to have normal Kupffer populations (Fig. 4C).…”

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

“…1,2 In the liver, both conventional NK cells and NKT cells are quite abundant, in contrast to the relatively small percentage of these cells in the peripheral lymphatics. [2][3][4][5][6] Although the underlying reason for this anatomically biased distribution has not been fully elucidated, NK and NKT cells have been shown to mediate cytolytic activity and to secrete cytokines, enabling them to perform distinct functions in response to infected cells and neoplastic cells.…”

“…[2][3][4][5][6] Although the underlying reason for this anatomically biased distribution has not been fully elucidated, NK and NKT cells have been shown to mediate cytolytic activity and to secrete cytokines, enabling them to perform distinct functions in response to infected cells and neoplastic cells. 4,5,7 Under various pathophysiological conditions, such as viral hepatitis, bacterial infection, and autoimmune liver disease, liver NK cells are activated by various cytokines, such as interleukin (IL)-2, IL-12, interferon (IFN)-␣/␤, and IFN-␥, secreted from a wide variety of cell types, including dendritic cells, macrophages, and NKT cells, and this activation enhances their cytotoxic capacity, 1,2,8 Activated liver NK cells target not only infected or transformed hepatocytes but also intact hepatocytes in a nonspecific fashion. 8 -10 Cytotoxicity of liver NK cells against normal hepatocytes seems excessive self-defense from the point of view of innate immunity.…”

Decrease of Cd56+T Cells and Natural Killer Cells in Cirrhotic Livers With Hepatitis C May Be Involved in Their Susceptibility to Hepatocellular Carcinoma

“…[9][10][11][12][13] Namely, mouse NK1.1 antigen ϩ T (NKT) cells and human CD56 ϩ T cells are abundant in the livers. NKT cells in mice were activated by IL-12 and inhibited tumor metastases in the liver of mice 10,11,[14][15][16] (for a review, see Seki et al, 16 ). Human peripheral blood CD56 ϩ T cells were also activated in vitro by IL-12 and thus acquired an antitumor cytotoxicity against NK-resistant tumors.…”

“…After washing 3 times with medium, the cells were resuspended in osmolarity-and pH-adjusted 33% Percoll solution containing 100 U/mL heparin and then were centrifuged at 2,000 rpm for 15 minute at room temperature. 14,16 The pellet was resuspended in a red blood cell lysis solution, then washed twice in 5% FBS RPMI. PBMC were obtained from blood samples using a Lymphocyte Separation Medium (ICN Biomedicals Inc., Aurora, OH).…”