A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions

Stephanie K. Lathrop, Cortny A. Huddleston, Per A. Dullforce, Megan J. Montfort, Andrew D. Weinberg, David C. Parker

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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-γ directly ex vivo, and the majority make IFN-γ 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-γ 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.

Original languageEnglish (US)
Pages (from-to)6735-6743
Number of pages9
JournalJournal of Immunology
Volume172
Issue number11
DOIs
StatePublished - Jun 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lathrop, S. K., Huddleston, C. A., Dullforce, P. A., Montfort, M. J., Weinberg, A. D., & Parker, D. C. (2004). A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. Journal of Immunology, 172(11), 6735-6743. https://doi.org/10.4049/jimmunol.172.11.6735