Loss of high affinity transforming growth factor-beta 1 (TGF-beta 1) binding to a nephritogenic T cell results in absence of growth inhibition by TGF-beta 1 and augmented nephritogenicity.

Abstract

Transforming growth factor-beta (TGF-beta) affects cellular proliferation and differentiation and has been linked to the development of pathologic extracellular matrix production characteristic of progressive renal disease. TGF-beta 1 is conventionally regarded as having growth-inhibitory activity on T lymphocytes. The growth-regulatory activity of TGF-beta 1 depends on the interaction of TGF-beta 1 with its receptors, especially the type I and II receptors. In this study, we describe a CD4+ nephritogenic T cell clone that, unlike a sister clone with an identical TCR Ag receptor, is not growth inhibited by TGF-beta 1, nor is its nephritogenicity affected by exogenous TGF-beta 1. Although this TGF-beta-resistant T cell clone expresses both type I and II TGF-beta receptors on the cell surface, the affinity of this interaction is markedly diminished compared with that of the sister T cell clone, which does undergo growth arrest in response to extracellular TGF-beta 1. The resistant T cell clone expresses one mutant allele for the type I TGF-beta receptor. This mutation consists of a leucine to glutamine substitution at codon 122, a conserved amino acid in the transmembrane domain. We speculate that this mutation alters the interaction between the type I and II TGF-beta receptors following recognition of ligand by the type II receptor.