Effects of cyclosporin A on IL-2 production and lymphocyte proliferation during infection of mice with lymphocytic choriomeningitis virus.
The immunosuppressive agent, cyclosporin A (CsA) blocks production of IL-2 by lymphocytes in vitro, and impairs immune responses in vivo. During infection of mice with lymphocytic choriomeningitis virus (LCMV), IL-2 is produced by spleen lymphocytes with a time course corresponding to that of T cell activation and proliferation, but distinct from NK cell activation and proliferation. To evaluate the requirement for IL-2 in supporting lymphocyte proliferation in vivo, and to investigate the mechanisms of CsA-induced immunosuppression, the effects of CsA on LCMV-elicited responses were examined. CsA had profound effects on lymphocyte expansion and CTL activation on day 7 postinfection, the peak of the T cell response to LCMV. Proliferation of both the CD4+ and CD8+ T cell subsets was affected. Inhibition of T cell expansion was accompanied by the inhibition of IL-2 production and IL-2 responsiveness. In situ hybridization revealed a 50% reduction in the percentage of cells transcribing IL-2, suggesting that CsA blocked IL-2 production at the level of gene transcription. Transcripts of the gene for the IL-2R p55 chain are also normally elevated during infection, and CsA treatment resulted in an 80% reduction in the percentage of cells transcribing this gene. A reduced responsiveness of freshly isolated cells to rIL-2 in vitro correlated with the reduction of IL-2 receptor gene transcription positive cells. In contrast to effects of the drug on T cells, the level of NK cell activation was not decreased as a result of CsA treatment. These observations suggest that the IL-2 produced by lymphocytes in vivo in response to virus infection is required to promote the T cell response to LCMV, but do not support a role for IL-2 in NK cell activation under the conditions examined. Furthermore, the data demonstrate the profound inhibition of lymphocyte proliferation induced by CsA treatment during an in vivo immune response.
Kasaian
M T
MT
Division of Biology and Medicine, Brown University, Providence, RI 02912.
Biron
C A
CA
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens; D003524:Cyclosporins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008809:Mice, Inbred C3H; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D003524:Cyclosporins; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2