Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.
Lee
Won-Woo
WW
Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA.
Yang
Zhi-Zhang
ZZ
Li
Guangjin
G
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019588:Aging, Premature / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology; D053282:CD27 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology
D053282:CD27 Ligand; D018106:CD28 Antigens; C505771:CD70 protein, human; D011948:Receptors, Antigen, T-Cell