CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation.
CD28 is the quintessential costimulatory molecule expressed on CD4(+) and CD8(+) T cells. During chronic infections and the normal aging process, CD28 expression is lost, compromising the functional activity of T cells. CD28 loss is promoted by replicative stress, particularly in the presence of tumor necrosis factor-alpha, owing to an inoperative CD28 initiator element. It is currently unknown whether CD28 loss is irreversible. The present study examined cytokines for their ability to reinduce CD28 expression. CD4(+)CD28(null) T cells constitutively expressed interleukin-12 (IL-12) alpha and beta receptors, which were functional and allowed for the up-regulation of the signal transducer and activator of transcription-4 (STAT-4)-dependent gene CD161. Costimulation of the T-cell and IL-12 receptors induced the transcription of CD28 in approximately 50% of CD4(+)CD28(null) T-cell clones and lines. IL-12 by itself did not restore CD28 expression. Up-regulation of CD28 after IL-12 exposure correlated with the reassembly of the CD28-initiator protein complex. The re-expressed CD28 was functional and restored the ability of CD4(+)CD28(null) T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4(+) T cells.
Warrington
Kenneth J
KJ
Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Vallejo
Abbe N
AN
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D012045:Regulatory Sequences, Nucleic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D018106:CD28 Antigens; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12