Local variations in proteasome composition might regulate organ-specific autoimmunity, according to a recent report in The Journal of Experimental Medicine.
Ulrike Kuckelkorn and colleagues set out to investigate why self-antigens that are expressed ubiquitously can drive organ-specific autoimmune responses. They used a mouse model in which T-cell-receptor-transgenic CD8+ T cells that cross-react with the ubiquitous self-antigen heat-shock protein 60 (Hsp60) are transferred into T-cell-deficient mice. The resulting autoimmune response is restricted to the small intestine, despite similar migration of transgenic T cells to the colon. The authors wondered if tissue-specific differences in the proteolytic processing of Hsp60 epitopes might account for this.
A key player in the generation of peptide epitopes that are recognized by CD8+ T cells is the proteasome, which consists of a cylindrical active core with a regulatory complex at each end. The core — which is known as the 20S proteasome — consists of two α-rings and two β-rings, each of which is formed by seven subunits. The basic 20S proteasome is expressed constitutively. However, interferon-γ induces the expression of components that replace the constitutive β-subunits; this forms the 'immunoproteasome', which has altered activities.
The authors examined the composition of 20S proteasomes from various tissues by two-dimensional gel electrophoresis. Comparing the small intestine with the colon, they found organ-specific expression patterns of the inducible β-subunits. Differentially expressed variants of α4 and α6 subunits (which interact with the regulatory complexes) were identified also.
Proteasomes from different organs were shown to have distinct cleavage-site preferences for the processing of Hsp60 in vitro. Notably, the Hsp60-derived peptide that is recognized by the pathogenic T cells was produced most efficiently by the proteasomes of the small intestine.
But, are the quantitative and qualitative differences in peptide production relevant to CD8+ T-cell recognition? This was tested in a chromium-release assay, in which target cells were pulsed with peptide products that had been generated in vitro by proteasomes isolated from various tissues. Only target cells that had been pulsed with peptides processed by small-intestine-derived proteasomes were lysed by the transgenic T cells.
The authors propose that this organ-specific generation of epitopes, “represents an important mechanism to control the reactivity of autoreactive CD8+ T cells that escape thymic deletion”.
ORIGINAL RESEARCH PAPER
Kuckelkorn, U. et al. Link between organ-specific antigen processing by 20S proteasomes and CD8+ T-cell-mediated autoimmunity. J. Exp. Med. 195, 983–990 (2002)
Kloetzel, M. P. Antigen processing by the proteasome. Nature Rev. Mol. Cell Biol. 2, 179–188 (2001)
Steinhoff, U. et al. Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells. Immunity 11, 349–358 (1999)