Characterization of the T cell recognition of hepatitis B surface antigen (HBsAg) by good and poor responders to hepatitis B vaccines

Abstract

SUMMARYTo study the regulation of the human cellular immune response to HBsAg we produced a series of HBsAg-specific T cell lines from good and poor responders to the hepatitis B vaccine. All T cell lines expressed CD4 on their membrane and could therefore be considered of the helper/inducer phenotype. The different HBsAg-specific T cell lines were restricted by HLA-DRB5*0101, DRB1*1201, -DRB1*0701, -DRB1*0301, -DPB1*0201, -DPB1*0402, and -DPB1*0901. In good responders to the hepatitis B vaccine different HLA molecules could act as restricting element. In poor responders the diversity of HLA class II restriction determinants was more limited. This leads us to conclude that the immune response to HBsAg is multispecific and polyclonal in good responders and paucispecific and oligoclonal in poor responders to the hepatitis B vaccine. By using a panel of synthetic peptides representing selected sequences of the HBsAg, the fine specificities of each of these T cell lines could be determined. Strikingly, the majority of the identified T cell epitopes was located in and around the first hydrophobic transmembranous region of the HBsAg. This was observed in T cell lines from good and poor vaccine responders, without distinction. The remarkable T cell immunogenicity of this region may reside in its richness in binding motifs for a variety of HLA class II determinants.

Gluten Intake Interferes With the Humoral Immune Response to Recombinant Hepatitis B Vaccine in Patients With Celiac Disease

“…Nonresponding patients may have a failure of major histocompatibility complex class II molecules in the interaction with processed protein antigen, in the stimulation of T-helper cells, or in both. 30,31 Godkin et al 19 investigated the binding affinities of envelope and core peptides of HBV to particular HLA glycoproteins, and their data supported the direct involvement of HLA-DR3 in HBV vaccine nonresponsiveness. The lack of response to HBsAg has been also attributed to defective or insufficient HBsAgspecific T-helper cells, 32,33 inadequate T-helper 1 and T-helper 2 cytokine production, [34][35][36] or diminished expression of cell-cell contact signals between activated T and B cells, like CD40L.…”

Kinetics of the immune response during HBV and HCV infection

“…Although the profile of the adaptive immune response against HBV and HCV infections is similar, the antiviral immune response can provide protection against HBV 122 but not against HCV reinfection. 123,124 Moreover, although a vaccine based on the envelope protein of HBV, which induces envelope-specific antibody 122 and helper T-cell responses, [125][126][127] can elicit a sterilizing anti-HBV immunity, different HCV vaccine preparations able to prime similar profiles of T-and B-cell responses have so far failed to protect animals from HCV infection. 128,129 The different kinetics of HCV and HBV replication may represent one of the factors responsible for these differences.…”

Non-responsiveness to hepatitis B surface antigen vaccines is not caused by defective antigen presentation or a lack of B7 co-stimulation

“…This and other [24] studies demonstrate that this phenomenon is due more probably to 'selective holes in the T cell recognition repertoire' than to inadequate Ag presentation by APC. To corroborate this hypothesis we previously examined whether HBsAg-specific T cells could be detected in DR3 and DR7 individuals [25]. We found DR3-and DR7-restricted HBsAg-specific T cells in these NR, but at very low frequency.…”

“…T cell non-response can result from the failure of APC to process a complex protein antigen (Ag) into one or more T cell epitopic peptides, to the inability of a given MHC class II molecule to bind a T cell epitopic peptide (presentation defect) or from the absence of T cells that can recognize a particular MHC-peptide complex (a hole in the T cell repertoire). Both defects have been proposed to explain NR to HBsAg vaccination in humans [23][24][25][26]. Previously, we performed T cell-APC mixing experiments using responder T cells and NR-APC and showed that HLA-DR7 + NR-APC were able to take up, process and present HBsAg [24].…”