The p55 TNF-α receptor plays a critical role in T cell alloreactivity

Geoffrey R. Hill, Takanori Teshima, Vivienne I. Rebel, Oleg I. Krijanovski, Kenneth R. Cooke, Yani S. Brinson, James L.M. Ferrara

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

TNF-α is known to be an important mediator of tissue damage during allograft rejection and graft-vs-host disease (GVHD), but its role in supporting T cell responses to allogeneic Ags is unclear. We have studied this question by comparing normal mice with those lacking the p55 (p55 TNFR(- /-)) or p75 (p75 TNFR(-/-)) TNF-α receptors as donors in well-defined bone marrow transplant (BMT) models. Recipients of p55 TNFR(-/-) cells had significantly reduced mortality and morbidity from GVHD compared with the other two sources of T cells. In vitro, T cells lacking the p55 (but not the p75) TNF-α receptor exhibited decreased proliferation and production of Th1 cytokines in MLC. This defect was only partially restored by exogenous IL-2 and affected both CD4+ and CD8+ populations. CD8+ p55 TNFR(-/-) proliferation was impaired independently of IL-2 whereas CTL effector function was impaired in an IL-2-dependent fashion. Inhibition of TNF-α with TNFR:Fc in primary MLC also impaired the proliferation and Th1 differentiation of wild-type T cells. BMT mixing experiments demonstrated that the reduced ability of p55 TNFR(-/-) donor cells to induce GVHD was due to the absence of the p55 TNFR on T cells rather than bone marrow cells. These data highlight the importance of TNF-α in alloreactive T cell responses and suggest that inhibition of the T cell p55 TNF-α receptor may provide an additional useful therapeutic maneuver to inhibit alloreactive T cell responses following bone marrow and solid organ transplantation.

Original languageEnglish (US)
Pages (from-to)656-663
Number of pages8
JournalJournal of Immunology
Volume164
Issue number2
DOIs
StatePublished - Jan 15 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hill, G. R., Teshima, T., Rebel, V. I., Krijanovski, O. I., Cooke, K. R., Brinson, Y. S., & Ferrara, J. L. M. (2000). The p55 TNF-α receptor plays a critical role in T cell alloreactivity. Journal of Immunology, 164(2), 656-663. https://doi.org/10.4049/jimmunol.164.2.656