Induction of sensitivity to activation-induced death in primary CD4+ cells: a role for interleukin-2 in the negative regulation of responses by mature CD4+ T cells.
We examine the requirements for converting naive, mature CD4+ cells from an activation-induced death (AID)-resistant to a -sensitive phenotype. Priming for sensitivity to AID can be divided into two steps. The first is a mitogen/CD3-dependent, cyclosporin-sensitive signal and the second a cytokine-dependent, cyclosporin-insensitive one. Under these conditions, interleukin (IL)-2, but not IL-4, IL-7 or IL-15, the receptors of which share a common receptor gamma chain, is capable of providing the cytokine signal for inducing sensitivity to AID. Increased expression of the low-affinity IL-2R alpha chain (CD25) is associated with acquisition of AID sensitivity and antibodies to CD25 block acquisition of AID sensitivity in the presence of IL-2. As with T cell hybridomas, AID is dependent on both CD95 and CD95 ligand (CD95L) expression, but unlike hybridomas, the sensitive and resistant phenotypes of primary CD4+ cells cannot be distinguished by levels of CD95 expression, functional CD95L nor the fraction of cells in cycle. The results suggest that the unique function of IL-2 is to regulate proteins, either not important or constitutively regulated in T cell hybridomas, that are essential for cell-autonomous suicide of activated CD4+ cells. These experiments provide a mechanism for the recent observations of chronic lymphoproliferation and autoimmune disease in mice with null mutations in IL-2 or CD25.
Wang
R
R
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis 63110, USA.
Rogers
A M
AM
Rush
B J
BJ
Russell
J H
JH
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D016193:G1 Phase; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D015375:Receptors, Interleukin-2 / Q000502:physiology; D016196:S Phase; D012680:Sensitivity and Specificity; D019014:fas Receptor / Q000032:analysis
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D015847:Interleukin-4