Activated T cells express the OX40 ligand: requirements for induction and costimulatory function.
OX40/OX40 ligand (OX40L) interactions have been shown to exert potent costimulatory effects on T-cell activation. OX40 expression is transiently up-regulated on T cells following T-cell receptor engagement, while OX40L is expressed on antigen-presenting cells following activation. Although expression of the OX40L by T cells has been reported, the requirements for induction of OX40L on T cells have not been studied in detail. Here, we demonstrate that the OX40L can be induced on murine CD4(+) and CD8(+) T cells after 6 days of culture under T helper type 1 (Th1) conditions, but not under Th2 conditions. Induction of OX40L expression required a high concentration of interleukin-12 (IL-12), was not seen in the presence of interferon-gamma, and was dependent on signal transducer and activator of transcription type 4 (STAT4). Notably, induction of OX40L on T cells was only seen at very low concentrations of antigen or anti-CD3. T-cell-expressed OX40L was fully capable of delivering a potent costimulatory signal that enhanced the proliferation of CD4(+) T cells as well as promoted their differentiation to Th2 cells. OX40L expression could also be induced on CD4(+) T cells in vivo following immunization with low-dose antigen and an IL-12 inducer. OX40/OX40L interactions between antigen-specific T cells may occur in T-cell zones in lymph node and spleen when OX40L expression has diminished on APC. Costimulation by T-cell-expressed OX40L may result in deviation of a Th1 response to a Th2 response under conditions where T cells are exposed to low concentrations of foreign or autoantigens in the presence of high concentrations of IL-12.
Mendel
Itzhak
I
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Shevach
Ethan M
EM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D050797:STAT4 Transcription Factor / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D050797:STAT4 Transcription Factor; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D007371:Interferon-gamma