Promotion of human T lymphocyte proliferation by IL-4.
The capacity of human rIL-4 to support the proliferation of mitogen-stimulated T cells directly as well as by increasing IL-2 production or enhancing IL-2 responsiveness was investigated. IL-4 augmented proliferation of T cells stimulated with PHA, Con A, immobilized mAb to the CD3 molecular complex (OKT3), or PMA. IL-4 increased the number of mitogen-stimulated cells entering the cell cycle as well as enhancing ongoing proliferation of mitogen-activated lymphoblasts. Facilitation of initial activation by IL-4 was not inhibited by mAb to the p55 component of the IL-2R, anti-Tac, and, therefore, was not dependent on endogenous IL-2 activity. However, IL-4-mediated enhancement of ongoing T cell proliferation stimulated by PHA or OKT3 was partially but not completely blocked by anti-Tac. Analysis of the supernatants from PHA-stimulated T cell cultures indicated that IL-4 increased the production of IL-2 by mitogen-activated cells. Moreover, IL-4 increased the amount of IL-2 mRNA that accumulated in mitogen-stimulated T cells. In addition, IL-4 markedly augmented IL-2R expression by PHA-stimulated T cells. Although IL-4 promoted ongoing DNA synthesis of mitogen-stimulated T cells in an IL-2-dependent manner, it was also able to sustain their proliferation directly. Thus, IL-4 supported proliferation of PMA-activated T cells in a manner that was not inhibited by anti-Tac. Furthermore, IL-4 could augment proliferation and IL-2R expression of T cells stimulated with PHA in the presence of cyclosporin A, which blocks endogenous cytokine production or anti-Tac. Finally, IL-4 was noted to enhance proliferation of both CD4+ and CD8+ T cell subsets. The results indicate that IL-4 enhances proliferation of mitogen-activated human T cells by a number of mechanisms, including the direct promotion of cell cycle entry and subsequent DNA synthesis, enhanced production of IL-2, and increased responsiveness to IL-2 in part by up-regulation of IL-2R expression.
Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235.
L C
LC
Mitchell
L S
LS
Davis
P E
PE
Lipsky
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000945:Antigens, Differentiation, T-Lymphocyte; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010641:Phenotype; D010835:Phytohemagglutinins; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D007378:Interleukins; D010835:Phytohemagglutinins; D015847:Interleukin-4; D004247:DNA