IFNγR signaling mediates alloreactive T-cell trafficking and GVHD

Jaebok Choi, Edward D. Ziga, Julie Ritchey, Lynne Collins, Julie L. Prior, Matthew L. Cooper, David Piwnica-Worms, John F. DiPersio

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR-/-) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNγR-/- Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNγR-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3-/- Tconv recapitulate the reduced GVHD potential of IFNγR-/- Tconv in a minor-mismatched GVHD model. Most importantly, IFNγR-/- (and CXCR3-/-) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNγR-/- regulatory T cells (Tregs) are fully suppressive in vitro although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (IFNγ), suggesting that the IFNγR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNγR signaling, results in the decreased expression of CXCR3 and reduced GVHD and improved survival after allo-HSCT and this effect is mediated by altered trafficking of Tconv to GVHD target organs.

Original languageEnglish (US)
Pages (from-to)4093-4103
Number of pages11
JournalBlood
Volume120
Issue number19
DOIs
StatePublished - Nov 8 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Choi, J., Ziga, E. D., Ritchey, J., Collins, L., Prior, J. L., Cooper, M. L., Piwnica-Worms, D., & DiPersio, J. F. (2012). IFNγR signaling mediates alloreactive T-cell trafficking and GVHD. Blood, 120(19), 4093-4103. https://doi.org/10.1182/blood-2012-01-403196