The self antigen heme evades immune recognition by sequestration in some hemoproteins.
Heme is a non-protein autoantigen which is ubiquitous in vivo, primarily complexed in various hemoproteins or bound to specialized carrier molecules. Nevertheless, heme is able to stimulate a high frequency of CD4+, class II-restricted T cells, freshly explanted from unprimed mice, to proliferate in vitro. In this study, we show that heme incorporated into various species of mammalian cytochrome c (cyt c), including murine cyt c, represents a facultative cryptic determinant, able to be recalled only at high doses of native cyt c. By contrast, avian cyt c is of comparable antigenicity to free heme. Artificially denatured carboxymethylated (CM) mammalian cyt c exhibited greatly increased antigenicity, comparable to that of heme and avian cyt c, indicating that the crypticity of heme in native mammalian cyt c is due to the resistance of the native conformation of this molecule to antigen processing within murine antigen-presenting cells. Thus, tolerance to the heme group of at least some hemoproteins, may be maintained by the crypticity of the heme, rather than by deletion of heme-reactive T cells. Given the high frequency of heme-reactive T cells in unprimed mice, these findings suggest that heme may become an important modulator during an inflammatory response.
Sutherland
R M
RM
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
Brassell
S
S
Liu
Q
Q
Paterson
Y
Y
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D002417:Cattle; D002645:Chickens; D010856:Columbidae; D003574:Cytochrome c Group / Q000737:chemistry / Q000276:immunology*; D006418:Heme / Q000276:immunology*; D006736:Horses; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000276:immunology; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D003574:Cytochrome c Group; D010446:Peptide Fragments; D006418:Heme