Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype.
We have investigated the effects of TGF-beta on the in vitro development of different subsets of Th cells and find that addition of TGF-beta results in the generation of cell populations with distinct characteristics that resemble those of memory cells. Resting, short-lived CD4+ precursor T cells can be induced by mitogen stimulation to proliferate and differentiate in in vitro cultures and after 4 to 7 days will generate a population of cells that, when restimulated, synthesize and secrete high titers of a wide variety of lymphokines. It has been previously reported that the presence of the lymphokine IL-4 during in vitro culture results in the generation of a population of "effector" cells that can be rapidly induced by mitogen to synthesize and secrete high titers of IL-4, IL-5, IL-3, IFN-gamma, and granulocyte-macrophage-CSF. We find that TGF-beta added to CD4+ precursors, suppresses the development of IL-4/IL-5 secreting effectors and results instead in the development of cells secreting IL-2 and IFN-gamma. CD4 T cells generated in the presence of TGF-beta show little or no expression of CD45RB, in contrast to those developed in IL-4 (or in IL-2 alone) that express high surface densities of CD45RB. The kinetics of cell recovery also differs when TGF-beta rather than IL-4 is present during culture. Cultures of effectors generated in TGF-beta, initially have low cell recoveries but cells expand dramatically between 4 to 7 days in the presence of IL-2 whereas IL-4 induces optimum cell recovery at day 4 and cell recoveries decrease with further culture. The properties of cells grown in TGF-beta thus show several attributes in common with memory or highly differentiated CD4+ cells, i.e., IL-2 as a predominant cytokine, easy propagation and low expression of CD45RB. Therefore, we propose the hypothesis that TGF-beta favors the development of a population(s) of Th cells that is likely to give rise to memory cells although IL-4 favors development of a short-lived effector population that secretes Th2 lymphokines.
Department of Biology, University of California, San Diego, La Jolla 92093.
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Swain
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Huston
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Tonkonogy
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Weinberg
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D015870:Gene Expression; D015847:Interleukin-4 / Q000494:pharmacology*; D007378:Interleukins / Q000502:physiology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000945:Antigens, Differentiation, T-Lymphocyte; D007378:Interleukins; D008222:Lymphokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4