COMPARTMENTALIZATION OF T-LYMPHOCYTES TO THE SITE OF DISEASE - INTRAHEPATIC CD4-CELLS SPECIFIC FOR THE PROTEIN-NS4 OF HEPATITIS-C VIRUS IN PATIENTS WITH CHRONIC HEPATITIS-C( T)

The adult liver is an organ without constitutive lymphoid components. Therefore, any intrahepatic T cell found in chronic hepatitis should h ave migrated to the liver after infection and inflammation. Because of the little information available on the differences between intrahepa tic and peripheral T cells, we used recombinant proteins of the hepati tis C virus (HCV) to establish specific T cell lines and clones from l iver biopsies of patients with chronic hepatitis C and compared them w ith those present in peripheral blood mononuclear cells (PBMC). We fou nd that the protein nonstructural 4 (NS4) was able to stimulate CD4+ T cells isolated from liver biopsies, whereas with all the other HCV pr oteins 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 tha t the 22 PBMC-derived T cell clones represent, at least, six distinct clonal populations that differ in major histocompatibility complex res triction 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 (TCR) variable and hypervariable re gions. Remarkably, none of the PBMC-derived clones has a TCR identical to the liver-derived clone, and even with polymerase chain reaction o ligotyping we did not find the liver-derived clonotypic TCR transcript in the PBMC, indicating a preferential intrahepatic localization of t hese T cells. Functionally, the liver-derived T cells provided help fo r polyclonal immunoglobulin (Ig)A production by B cells in vitro that is 10-fold more effective than that provided by the PBMC-derived clone s, whereas there is no difference in the help provided for IgM and IgG production. Altogether these results demonstrate that the protein NS4 is highly immunogenic for intrahepatic CD4+ T cells primed by HCV in vivo, and that there can be compartmentalization of some NS4-specific CD4+ T cells to the liver of patients with chronic hepatitis C.