The Journal of Experimental Medicine
StemCell Technologies
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Published 20 June 2005. doi:10.1084/jem.20050419
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 12, 1925-1935
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ARTICLE

 IFN-{gamma} production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo

Birgit Sawitzki1,2, Cherry I. Kingsley1, Vanessa Oliveira1, Mahzuz Karim1, Manuela Herber1, and Kathryn J. Wood1

1 Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, England, UK
2 Institute of Medical Immunology, Charité, 10117 Berlin, Germany

CORRESPONDENCE Birgit Sawitzki: birgit.sawitzki{at}charite.de

The significance of cytokine production by CD4+ regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RBhighCD4+ T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25+CD4+ T cells, but not CD25–CD4+ T cells, showed a fivefold increase in IFN-{gamma} mRNA expression within 24 h of reencountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-{gamma} at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RBhighCD4+ effector T cells into Rag–/– skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-{gamma}–deficient mice. These data support a unique role for IFN-{gamma} in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.

Abbreviations used: EAE, experimental autoimmune encephalomyelitis; IDO, indoleamine-2,3-dioxygenase; iNOS, inducible nitric oxide synthase; MST, mean survival time; STAT1, signal transducer and activator of transcription–1; T reg, regulatory T.

B. Sawitzki, C. Kingsley, and V. Oliveira contributed equally to this work.


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