Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C.

Abstract

SllmmRryThe adult liver is an organ without constitutive lymphoid components. Therefore, any intrahepatic T cell found in chronic hepatitis should have migrated to the liver after infection and inflammation. Because of the little information available on the differences between intrahepatic and peripheral T cells, we used recombinant proteins of the hepatitis C virus (HCV) to establish specific T cell lines and clones from liver biopsies of patients with chronic hepatitis C and compared them with those present in peripheral blood mononuclear cells (PBMC). We found that the protein nonstructural 4 (NS4) was able to stimulate CD4 + T cells isolated from liver biopsies, whereas with all the other HCV proteins we consistently failed to establish liver-derived T cell lines from 16 biopsies. We then compared NS4-specific T cell clones obtained on the same day from PBMC and liver of the same patient. We found that the 22 PBMC-derived T cell clones represent, at least, six distinct clonal populations that differ in major histocompatibility complex restriction and response to superantigens, whereas the 27 liver-derived T cell clones appear all identical, as further confirmed by cloning and sequencing of the T cell receptor (TCK) variable and hypervariable regions. Remarkably, none of the PBMC-derived clones has a TCK identical to the liver-derived clone, and even with polymerase chain reaction oligotyping we did not find the liver-derived clonotypic TCK transcript in the PBMC, indicating a preferential intrahepatic localization of these T cells. Functionally, the liver-derived T cells provided help for polyclonal immunoglobulin (Ig)A production by B cells in vitro that is 10-fold more effective than that provided by the PBMC-derived clones, whereas there is no difference in the help provided for IgM and IgG production. Altogether these results demonstrate that the protein Ng4 is highly immunogenic for intrahepatic CD4 + T cells primed by HCV in vivo, and that there can he compartmentalization of some NS4-specific CD4 + T cells to the liver of patients with chronic hepatitis C.

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

“…In line with other reports (Minutello et al 1993, Sakai et al 1999, Exley et al 2002, our results demonstrate the compartmentalised nature of the immune response to HCV. The correlation between periportal activity and portal CD4 + , as seen in a preliminary study (Viso et al …”

Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C

“…This concept of "original antigenic sin" has been shown to occur after sequential infection of mice with two similar strains of lymphocytic choriomeningitis virus, but has not been demonstrated in evolution from acute to chronic infection. 48 Anti-HCV immune responses may also be compartmentalized to the liver, as some studies suggest, [49][50][51] although others have found that specificities in the 2 compartments are similar, and studies of intrahepatic lymphocyte responses during acute human HCV infection are lacking. Recent evidence suggests that CD4ϩ T cell help is required for efficient development of effector and memory CD8 T cell populations in HIV infection, 52 and when lacking may facilitate viral escape mutation in HCV infection.…”

CD4+/CD8+ ratio of liver-derived lymphocytes is related to viraemia and not to hepatitis C virus genotypes in chronic hepatitis C

“…Previous studies have reported that HCV-specific T lymphocytes could be detected among liver-infiltrating lymphocytes. CD4* T cells specific for the NS4 protein of HCV were derived from the liver tissue of patients with chronic hepatitis C, and appeared to compartmentalize at the site of disease [18]. In addition.…”

“…In patients with chronic hepatitis C, HCV-specific T lymphocytes have been found in the peripheral blood, and HCV cytotoxic T cell response has been found to be MHC class I-restricted [15.16]. In addition, several studies have shown that HCV-specific T lymphocytes are present among liver-derived lymphocytes [17,18], thereby emphasizing that T cell response may be a main counterpart of the itnniune response to HCV infection.…”