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The liver has specific mechanisms to protect itself from infectious agents and to avoid autoimmunity, indicating an important role of the hepatic tissues in antigen presentation and tolerance induction. Since intrahepatic lymphocytes may contribute to the innate immunity and to the liver pathology, it is of interest to analyze the expression of antigen presenting molecules and of the related T cell recognition in liver, and how these change in relation to different diseases. We analyzed the expression of MHC class I, and of CD1-a, -b, -c, and -d proteins on liver tissues from patients with different hepatic diseases. Moreover, in the same patients we studied the intrahepatic and peripheral NKT cell recognition of alpha-galactosyl ceramide antigen in the context of CD1d. Unlike in other tissues, classical MHC class I molecules were poorly expressed in the hepatic compartment, suggesting that inflamed hepatocytes may trigger weak MHC-restricted T cell responses. Nevertheless, we observed a prevalent expression of HLA class I-like CD1d isoform on the hepatocyte surface, indicating that CD1d is the main restriction element in the liver. In patients with viral hepatitis, the intrahepatic CD1d expression parallels the recruitment of CD56+Valpha24Vbeta11+ NKT cells in the liver which recognize CD1d presenting glycolipids such as alpha-galactosyl ceramide, suggesting that the intrahepatic T cell immunity may focus on glycolipid antigens.

Gammadelta T lymphocytes recognize nonpeptidic microbial antigens without MHC restriction and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. This innate recognition involves both T Cell Receptor (TCR) and NK-receptor mediated signalling through non-peptidic metabolites and HLA class I down-regulation. We observed that HLA-masking and nonpeptidic phosphoantigens induce the expression of CD25 and CD69 activation markers on the surface of gammadelta T cells. Interestingly, CD94+ cell depletion by magnetic beads showed that the expression of this antigen is essential for Vdelta2 T cell activation by HLA-masking. Moreover, both phosphoantigen-stimulation and in vitro HIV infection resulted in marked Vgamma9Vdelta2 T cell expansion, whereas HLA-masking was unable to induce proliferative responses. Finally, we observed a relevant hyporesponsiveness to non-peptidic antigens in HIV-infected persons and in cord blood cells from healthy donors when compared to adult PBMC from uninfected donors. Altogether, the reduced ability to naturally recognize the infected cells may contribute to HIV-disease progression and may facilitate maternal transmission of HIV infections.

A subset of patients treated with recombinant interferon alpha-2a (rIFN-alpha 2a) for idiopathic mixed cryoglobulinemia (IMC) developed clinical resistance to therapy after a sustained response. Neutralizing antibodies to rIFN-alpha 2a were found in the sera of three out of four such patients, and in none of the patients who remained responsive to treatment. rIFN-alpha 2a neutralizing antibodies appeared in serum samples of the former three patients 1, 5 and 6 months before evidence for clinical resistance, respectively. Antibody titres to rIFN-alpha 2a were consistently higher than those to natural interferon (nIFN). In the fourth patient with clinical resistance, neutralizing antibodies could not be detected by a very sensitive bioassay in any of several serum samples taken before and after relapse. All the four patients could be reinduced into remission by the administration of nIFN-alpha. These data indicate that mechanisms other than the production of neutralizing antibodies can mediate acquired resistance to IFN therapy. Furthermore, both antibody-related and -unrelated resistance can be overcome by switching to different species of IFN-alpha.