A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions.
To study mechanisms of peripheral self-tolerance, we injected small numbers of naive CD4(+) TCR-transgenic T cells into mice expressing the MHC/peptide ligand under the control of an MHC class II promoter. The donor T cells expand rapidly to very large numbers, acquire memory markers, and go out into tissues, but the animals remain healthy, and the accumulated T cells are profoundly anergic to restimulation with Ag in vitro. Provision of a costimulatory signal by coinjection of an agonist Ab to OX40 (CD134), a TNFR family member expressed on activated CD4 T cells, results in death of the mice within 12 days. TCR-transgenic T cells recovered at 5 days from anti-OX40-treated mice have a unique phenotype: they remain unresponsive to Ag in vitro, but they are larger, more granular, and strongly IL-2R positive. Some spontaneously secrete IFN-gamma directly ex vivo, and the majority make IFN-gamma in response to PMA and ionomycin. Although they are anergic by conventional tests requiring Ag recognition, they respond vigorously to cytokines, proliferating in response to IL-2, and secreting IFN-gamma when TCR signaling is bypassed with IL-12 and IL-18. We conclude that the costimulatory signal through OX40 allows otherwise harmless, proliferating, autoreactive T cells to acquire effector cell functions. The ability of these T cells to respond to cytokines by synthesizing additional inflammatory cytokines without a TCR signal may drive the fatal pathogenic process in vivo.
Lathrop
Stephanie K
SK
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239, USA.
Huddleston
Cortny A
CA
Dullforce
Per A
PA
Montfort
Megan J
MJ
Weinberg
Andrew D
AD
Parker
David C
DC
D000818:Animals; D019013:CD40 Antigens / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D019013:CD40 Antigens; D020382:Interleukin-18; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma