Vitamin A down-regulation of IFN-γ synthesis in cloned mouse Th1 lymphocytes depends on the CD28 costimulatory pathway

Margherita T. Cantorna, Faye E. Nashold, Tae Yon Chun, Colleen E. Hayes

Research output: Contribution to journalArticle

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Abstract

Some infections deplete serum retinol, low retinol reduces immunity, and reduced immunity establishes susceptibility to further infection in a cyclical relationship that is poorly understood. We showed that when retinol was low, there was excessive Th1 cell IFN-γ synthesis and inadequate Th2 cell IL-4 and IL-5 synthesis. The retinol metabolite retinoic acid inhibited the IFN-γ stimulatory activity of APCs, enhanced Th2 cell differentiation, and inhibited Th1 cell IFN-γ synthesis. Here we focus on the mechanism for retinoic acid inhibition of IFN-γ synthesis in myelin basic protein-specific MM4 Th1 cells. Physiologic amounts of all-trans-retinoic acid directly and specifically down-regulated the MM4 Th1 cell IFN-γ secretion rate in vitro without affecting cell growth, viability, or overall protein synthesis. All-trans-, 9-cis-, and 13-cis-retinoic acid, and the synthetic retinoid Ch55, inhibited IFN-γ synthesis effectively, whereas retinaldehyde, retinol, and retinyl acetate did not. This pattern suggests retinoic acid receptor involvement in the inhibition mechanism. Retinoic acid did not inhibit when Th1 cells were activated only through the TCR/CD3 complex, with or without IL-2 costimulation. Retinoic acid inhibited IFN-γ synthesis when the CD28 costimulatory pathway was activated in addition to the TCR/CD3 pathway, suggesting it blocks some step in the CD28 pathway. Retinoid probably acted to decrease IFN-γ transcript accumulation by decreasing transcription because it did not decrease transcript stability. We suggest that unrestrained IFN-γ synthesis is one key immunobiologic mechanism that accounts for poor antibody-mediated immunity in hypovitaminosis A, since IFN-γ in relatively small amounts can limit Th2 cell growth and interfere with the B cell stimulatory functions of Th2 cell cytokines.

Original languageEnglish (US)
Pages (from-to)2674-2679
Number of pages6
JournalJournal of Immunology
Volume156
Issue number8
StatePublished - Apr 15 1996

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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