Skip Navigation


International Immunology Advance Access originally published online on March 14, 2008
International Immunology 2008 20(5):633-644; doi:10.1093/intimm/dxn023
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
20/5/633    most recent
dxn023v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Metzler, B.
Right arrow Articles by Brinkmann, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Metzler, B.
Right arrow Articles by Brinkmann, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure

Barbara Metzler1, Patrick Gfeller1, Grazyna Wieczorek1, Jianping Li1, Barbara Nuesslein-Hildesheim1, Andreas Katopodis1, Matthias Mueller2 and Volker Brinkmann1

1 Department of Autoimmunity and Transplantation
2 Models of Disease Center, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland

Correspondence to: B. Metzler; E-mail: barbara.metzler{at}novartis.com

The immunomodulator FTY720 inhibits lymph node (LN) and thymic egress, thereby constraining T cell circulation and reducing peripheral T cell numbers. Here, we analyzed in mouse models the as yet scarcely characterized impact of long-term (up to 6 months) FTY720 exposure on T cell homeostasis and possible consequences for alloreactivity. In green fluorescent protein (GFP) hemopoietic chimeras, the turnover of (initially GFP–) peripheral T cell pools was markedly delayed under FTY720, while normal homeostatic differences between CD4 and CD8 T cell sub-populations were retained or amplified further. Homeostatic proliferation was enhanced, and within shrinking T cell pools, the proportions of effector memory phenotype CD4 T cells (CD4TPEM) increased in spleens and LNs and of central memory phenotype CD8 T cells (CD8TPCM) in LNs. By contrast, the fractions of CD8TPEM and CD4TPCM remained stably small under FTY720. The enrichment for CD4TPEM and CD8TPCM correlated with larger proportions of IFN{gamma}-producing T cells upon nonspecific but not allospecific stimulation. Splenic CD4 T cells from FTY720-treated mice proliferated more strongly upon transfer to semi-allogeneic hosts. However, heart allograft survival was not compromised in FTY720 pre-treated recipients. It correlated with reduced intra-graft CD8 T cells, and the longest surviving transplants contained the highest numbers of CD4 T cells. Thus, continuous FTY720 exposure reveals differential homeostatic responses by memory phenotype CD4 and CD8 T cell sub-populations, and it may enhance alloreactive CD4 T cell proliferation and tissue infiltration without accelerating allograft rejection.

Keywords: homeostatic proliferation, sphingolipid mediators, T cell memory, transplantation

Transmitting editor: A. Cooke

Received 22 October 2007, accepted 8 February 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.