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International Immunology Advance Access originally published online on March 14, 2008
International Immunology 2008 20(5):633-644; doi:10.1093/intimm/dxn023
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© 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.


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