Defining T Cell Receptors which Recognise the Immunodominant Epitope of the Gastric Autoantigen, the H/K ATPase β-Subunit

Abstract

We have previously shown that autoimmune gastritis can be elicited in mice by immunisation with the gastric parietal cell H/K ATPase αβ heterodimer, and, furthermore, have identified the H/K ATPase β-subunit epitope, H/Kβ253-277 as the dominant epitope of the gastric H/K ATPase. Using gastric H/K ATPase-immunised mice, here we have generated two T cell hybridomas specific for the H/Kβ253-277 peptide, namely 4B11.F4.5 and 1E4.C1. Hybridoma 4B11.F4.5 uses Vα8 and Vp8.2 TCR chains and 1E4.C1 uses Vα9 and Vβ8.3 chains. Although both hybridomas are specific for H/Kβ253-277. T cell assays using overlapping 14-mers of the 25-mer epitope showed that the two autoreactive TCRs recognise different regions of the 25-mer. The TCR from 1E4.C1 has been used to generate a TCR β-chain transgenic mouse. $80% of peripheral CD4+ T cells utilise the Vβ8.3 transgene. As expected, 1E4-TCR (3-chain transgenic mice are susceptible to neonatal thymectomy induced autoimmune gastritis. While none of the 1E4-TCR β chain transgenic mice spontaneously developed a destructive gastritis, a minority (20%) of the transgenic mice developed a non-invasive and non-destructive gastritis. This suggests that the pathogenic T cells are maintained in a tolerant state in the periphery of the transgenic mice