Cell surface CD28 levels define four CD4(+) T cell subsets: Abnormal expression in rheumatoid arthritis

CD28 is a costimulatory receptor expressed in most CD4(+) T cells. Despite the long-standing evidence for up- and downregulation of surface CD28 expre ssion in vitro, and the key regulatory role assigned to the upregulation of CD28 counterreceptor [the CD152 (CTLA-4) molecule], in vivo CD28 induction has attracted little attention. We studied CD28 and CD152 expression and f unction in 33 rheumatoid arthritis (RA) patients, 20 clinically active and 13 inactive, and in 24 healthy donors. Four subsets of CD28(-), CD28(low), CD28(int), and CD28(high) peripheral blood human CD4(+) T cells were define d using three-color flow cytometry, The three CD28(+) subsets displayed a o ne-, two-, or threefold quantitative difference in their relative number of CD28 antibody binding sites, respectively (P < 0.01), RA patients, whether active or inactive, showed a distinct phenotype when compared to healthy d onors: (i) the percentage of CD4(+)CD28(high) cells was increased twofold a nd the CD4(+)CD281(low) subset was reduced twofold (P < 0.01) and (ii) the CD4(+)CD28(high) cells from RA patients showed an in vivo activated phenoty pe, CD45RO(+)CD5(high)IL-2R alpha (+) (P < 0.01). Active RA patients were d ifferent from inactive patients. They showed a twofold increase in mean CD2 8 expression (P < 0.05), whereas each of the CD28(+) subsets in the inactiv e RA patients showed reduced expression when compared to healthy donors, No tably, both active and inactive RA patients showed abnormal CD28 upregulati on when T cells were activated in vitro with CD3 antibodies, but only inact ive RA. patients showed a hypoproliferative response to TCR/CD3 triggering when compared to healthy donors (P < 0.01), This defective proliferation wa s normalized by concurrent crosslinking with CD28 antibody, No differences were noted in the expression of CD152 or CD80, a CD28 and CD152 shared liga nd. The disregulated in vivo expression of CD28 was related to the RA patie nts' disease activity and suggests that modulation of CD28 surface levels m ay be an additional mechanism to finely tune the delicate responsiveness/to lerance balance. (C) 2001 Academic Press.