Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28- T cells from rheumatoid arthritis patients.
Patients with rheumatoid arthritis have a subset of CD4+ T lymphocytes that are characterized by a defect in CD28 expression. CD4+CD28- T cells frequently undergo clonal expansion in vivo. These clonotypes include autoreactive cells and persist over many years. The clonogenic potential and longevity of these T cells could be related to an altered response to apoptosis-inducing signals. To explore this possibility, CD4+CD28- T cell lines and clones were examined for their response pattern to stimuli inducing physiologic cell death. CD4+CD28- T cells were found to be resistant to apoptosis upon withdrawal of the growth factor, IL-2. To examine whether the altered sensitivity to this apoptotic signal was correlated with the expression of proteins of the bcl-2 family, the expression of bcl-2, bcl-x, and bax proteins was determined. CD28+ and CD28-CD4+ T cells could not be distinguished by the levels of bax or bcl-xL protein; however, CD4+CD28- T cells expressed higher amounts of bcl-2 protein than did CD4+CD28+ T cells. The increased bcl-2 expression in CD4+CD28- T cells was relatively independent of signals provided by exogenous IL-2. In CD28-deficient CD4+ T cells, bcl-2 was not significantly up-regulated by the addition of exogenous IL-2 and was maintained despite IL-2 withdrawal, as opposed to CD28-expressing CD4+ T cells. We propose that CD4+CD28- T cells are characterized by a dysregulation of the survival protein, bcl-2, which may favor the clonal outgrowth of autoreactive T cells and thus contribute to the pathogenesis of rheumatoid arthritis.
Department of Medicine, Division of Rheumatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
M
M
Schirmer
A N
AN
Vallejo
C M
CM
Weyand
J J
JJ
Goronzy
D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D015704:CD4 Antigens; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2