Broad programming by IL-2 receptor signaling for extended growth to multiple cytokines and functional maturation of antigen-activated T cells.
Coincident production of IL-2 and induction of high-affinity IL-2R upon TCR engagement has precluded a clear distinction for the biological outcome of signaling through TCR/costimulatory molecules vs the IL-2R. Using a novel transgenic mouse on the IL-2Rbeta(-/-) genetic background, this study has separated the relative outcome of signaling through the TCR and IL-2R. We show that stimulation through the TCR and CD28 or CD40 ligand directly leads to T cell activation and several rounds of proliferation in an IL-2-independent fashion. However, this stimulation is insufficient for extended T cell growth to multiple cytokines or differentiation into CTL or IFN-gamma-secreting effector T cells. IL-2 is required for these functions in part by regulation of cyclin D3 and granzyme B. Somewhat less efficiently, IL-4 stimulation of these transgenic T cells redundantly rescued many of these activities. These data demonstrate a fundamental requirement for IL-2 and perhaps other common gamma-chain-dependent cytokines to promote selective gene expression by Ag-activated T cells for their subsequent growth and differentiation into effector T lymphocytes.
Malek
T R
TR
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA. tmlek@med.miami.edu
Yu
A
A
Scibelli
P
P
Lichtenheld
M G
MG
Codias
E K
EK
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019948:Receptors, Interleukin-4 / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D018797:Cell Cycle Proteins; D016207:Cytokines; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D015847:Interleukin-4