Keratinocyte-derived T cell costimulation induces preferential production of IL-2 and IL-4 but not IFN-gamma.
By using superantigens, we have found previously that keratinocytes activated by IFN-gamma could serve as accessory cells, providing costimulatory signals needed to induce T cell proliferation. Here, we compared the profile of cytokines produced by T cells stimulated in the presence of activated keratinocytes with the response seen using professional APCs. When keratinocytes are used as accessory cells there is a specific defect in T cell IFN-gamma production, whereas IL-2 and IL-4 are induced at levels comparable with those seen when professional APCs are used as accessory cells. Because keratinocytes express BB-1, a CD28-ligand distinct from B7-1 or B7-2 (which are found on professional APCs), we examined the possibility that the defect in IFN-gamma production might be a result of nonproductive CD28 engagement. However, even when the CD28 pathway is directly activated by a stimulatory mAb, there is no induction of IFN-gamma production in keratinocyte-supported cultures. In these same cultures IL-2 production is increased 10-fold, thus demonstrating a specific deficiency in the induction of IFN-gamma rather than a failure to respond to CD28 stimulation. Analysis by reverse transcriptase-PCR and ELISA for the inducible p40 chain of IL-12 reveals that keratinocytes produce little if any messenger RNA and no protein for IL-12 p40 compared with professional APCs. Addition of rIL-12 to keratinocyte-supported cultures restores IFN-gamma levels to those seen when professional APCs are present. Finally, when T cells are restimulated and analyzed at later time points (10 to 14 days) we find a refinement in cytokine profiles: T cells stimulated in the presence of professional APCs produced the Th1 cytokines IL-2 and IFN-gamma, whereas T cells stimulated in the presence of activated keratinocytes produced only the Th2 cytokine IL-4. The specific ability of keratinocytes to induce a Th2 response seems most closely linked to their absence of IL-12 production, and may be important in the maintenance of peripheral tolerance to self-Ags or in the immune response to exogenous Ags, pathogens, or haptens encountered in skin.
Goodman
R E
RE
Department of Medicine, University of Michigan, Ann Arbor 48109.
Nestle
F
F
Naidu
Y M
YM
Green
J M
JM
Thompson
C B
CB
Nickoloff
B J
BJ
Turka
L A
LA
D000938:Antigen-Presenting Cells / Q000502:physiology; D001483:Base Sequence; D018106:CD28 Antigens / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12; D007376:Interleukin-2 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000502:physiology; D015603:Keratinocytes / Q000502:physiology*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000502:physiology*
D018106:CD28 Antigens; D007376:Interleukin-2; D007378:Interleukins; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma