Chronic viral hepatitis patients, especially hepatitis C patients, often fall victim to liver cirrhosis and subsequent hepatocellular carcinoma (HCC). 1 It is now believed that the HCV infection in hepatocytes itself is not cytopathic whereas the cellular immune response to infected hepatocytes may indeed cause hepatocyte injury. 1 It has been suggested that nonspecific NK cell activation 1,2 and viral antigen-specific activation of either CD4 ϩ T cells or cytotoxic CD8 ϩ T cells may be responsible for hepatocyte injury. 1,3-6 Consistent with this hypothesis, it has also been reported that liver lymphocytes expressed T helper 1 cytokine, IFN-␥, and IL-2 messenger RNA, and the serum levels of these cytokines were elevated in the patients with HCV. 7,8 On the other hand, livers from mice and humans have recently been reported to contain not only a large population of NK cells but also of T cells with NK cell markers. 9-13 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 10,11,14-16 (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. 13 Furthermore, strongly activated mouse liver NKT cells destroyed the syngeneic hepatocytes. 17 Therefore, the possibility has been raised that human CD56 ϩ T cells may also play an important role in both hepatocyte injury in chronic viral hepatitis and antitumor immunity in the liver. In the present study, we show that human liver MNC activated by anti-CD3 Ab or a combination of IL-2 and IL-12 (or IL-2 alone) both produced IFN-␥ and killed tumors more effectively than did PBMC. Furthermore, human liver CD56 ϩ T cells and CD56 ϩ NK cells gradually decreased in parallel with the progress of the hepatitis C and diminished in livers with cirrhosis. These liver MNC from cirrhotic livers could not effectively produce IFN-␥ and could not effectively kill not only K562 cells and Raji cells but also a human HCC cell line, HuH-7 cells, thus suggesting that the decrease in CD56 ϩ T cells and NK cells may be one of the mechanisms explaining why HCC frequently originates from cirrhotic livers. PATIENTS AND METHODSPatients and Liver Specimens. Liver specimens were obtained during surgery from the patients listed in Table 1 after obtaining their informed consent. Liver specimens obtained from the anti-HCV Aband HBs antigen (Ag)-negative patients with cancers other than HCC and were regarded as the HCV (Ϫ) liver specimens. Other liver specimens were from anti-HCV Ab-positive patients with chronic hepatitis C or with liver cirrhosis. Peripheral blood samples were also obtained during surgery. All liver specimens were obtained from areas other than tumor nodules.Reagents. Anti-CD3 Ab (UCHT1, mouse IgG1) were purchased from PharMingen (San Diego, CA). Recombinant human IL-2 and IL-12 were purchased from PEPRO TECH EC (London, UK). ...
SUMMARY+ T cells>CD57 + T cellsiCD8 + T cellsiNK cells. However, the CD3-stimulated proliferation of both NK-type T cells was smaller than that of CD8 + T cells partly because NK-type T cells were susceptible to apoptosis. In addition to NK cells, NK-type T cells but not CD8+ T cells stimulated with cytokines, expressed cytoplasmic perforin and granzyme B. Furthermore, CD3-stimulated IFN-c production from peripheral blood mononuclear cells (PBMC) correlated with the proportions of CD57 + T cells in PBMC from donors. Our ®ndings suggest that NK-type T cells play an important role in the T helper 1 responses and the immunological changes associated with ageing.
NC/Nga (NC) mice raised under conventional conditions (Conv. NC mice) spontaneously develop dermatitis similar to human atopic dermatitis, whereas NC mice raised under the specific pathogen-free conditions do not develop dermatitis. In the present study, we show that the representative Th1 cytokine, IFN-γ levels in the sera of NC mice, injected with either staphylococcal enterotoxin B or endotoxin (LPS), to be severalfold lower than those of normal mice. The low IFN-γ response to staphylococcal enterotoxin B was correlated to the lack of regular Vβ8+ T cells and Vβ8+ NK T cells, and the low IFN-γ response to LPS was correlated to an impaired IL-18 production of macrophages. The CD3-stimulated IL-4 production from liver and spleen T cells from Conv. NC mice in vitro was greatly augmented. The serum IL-4 levels of untreated Conv. NC mice also were higher than those of normal mice and specific pathogen-free NC mice. Treatment of Conv. NC mice either with IFN-γ, IL-12, or IL-18 twice a week from 4 wk of age substantially inhibited the elevation of the serum IgE levels, serum IL-4 levels, and dermatitis, and IL-12 or IL-18 treatment also reduced the in vitro IL-4 production from CD3-stimulated liver T cells. The systemic deficiency in the Th1 response to bacterial stimulation thus leads to a Th2-dominant state and may induce an abnormal cellular immune response in the skin accompanied with an overproduction of IgE and a susceptibility to dermatitis in NC mice.
Hosts after severe burn injury are known to have a defect in the Th1 immune response and are susceptible to bacterial infections. We herein show that liver NK cells are potent IFN-γ producers early after burn injury. However, when mice were injected with LPS 24 h after burn injury, IFN-γ production from liver mononuclear cells (MNC; which we previously showed to be NK cells) was suppressed, and the serum IFN-γ concentration did not increase, while serum IL-10 conversely increased compared with control mice. Interestingly, a single injection of IL-18 simultaneously with LPS greatly restored the serum IFN-γ concentration in mice with burn injury and also increased IFN-γ production from liver MNC. Nevertheless, a single IL-18 injection into mice simultaneously with LPS was no longer effective in the restoration of serum IFN-γ and IFN-γ production from the liver MNC at 7 days after burn injury, when mice were considered to be the most immunocompromised. However, IL-18 injections into mice on alternate days beginning 1 day after burn injury strongly up-regulated LPS-induced serum IFN-γ levels and IFN-γ production from liver and spleen MNC of mice 7 days after burn injury and down-regulated serum IL-10. Furthermore, similar IL-18 therapy up-regulated serum IFN-γ levels in mice with experimental bacterial peritonitis 7 days after burn injury and greatly decreased mouse mortality. Thus, IL-18 therapy restores the Th1 response and may decrease the susceptibility to bacterial infection in mice with burn injury.
Although CD8+ IL-2Rβ (CD122)+ T cells with intermediate TCR reportedly develop extrathymically, their functions still remain largely unknown. In the present study, we characterized the function of CD8+ CD122+ T cells with intermediate TCR of C57BL/6 mice. The proportion of CD8+ CD122+ T cells in splenocytes gradually increased with age, whereas CD8+ IL-2Rβ-negative or -low (CD122−) T cells conversely decreased. The IFN-γ production from splenocytes stimulated with immobilized anti-CD3 Ab in vitro increased with age, whereas the IL-4 production decreased. When sorted CD8+ CD122+ T cells were stimulated in vitro by the anti-CD3 Ab, they promptly produced a much larger amount of IFN-γ than did CD8+ CD122− T cells or CD4+ T cells, whereas only CD4+ T cells produced IL-4. The depletion of CD8+ CD122+ T cells from whole splenocytes greatly decreased the CD3-stimulated IFN-γ production and increased the IL-4 production, whereas the addition of sorted CD8+ CD122+ T cells to CD8+ CD122+ T cell-depleted splenocytes restored the IFN-γ production and partially decreased IL-4 production. It is of interest that CD8+ CD122+ T cells stimulated CD4+ T cells to produce IFN-γ. The CD3-stimulated IFN-γ production from each T cell subset was augmented by macrophages. Furthermore, CD3-stimulated CD8+ CD122+ T cells produced an even greater amount of IFN-γ than did liver NK1.1+ T cells and also showed antitumor cytotoxicity. These results show that CD8+ CD122+ T cells may thus be an important source of early IFN-γ production and are suggested to be involved in the immunological changes with aging.
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