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Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure.

Metzler, Barbara and Gfeller, Patrick and Wieczorek, Grazyna and Li, Jianping and Nuesslein-Hildesheim, Barbara and Katopodis, Andreas and Mueller, Matthias and Brinkmann, Volker (2008) Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure. International Immunology, 20 (5). pp. 633-644. ISSN 1460-2377

Abstract

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 (CD4T(PEM)) increased in spleens and LNs and of central memory phenotype CD8 T cells (CD8T(PCM)) in LNs. By contrast, the fractions of CD8T(PEM) and CD4T(PCM) remained stably small under FTY720. The enrichment for CD4T(PEM) and CD8T(PCM) correlated with larger proportions of IFNgamma-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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher version cannot be used except for Nucleic Acids Research articles
Keywords: homeostatic proliferation; sphingolipid mediators; T cell memory; transplantation
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Date Deposited: 14 Dec 2009 13:52
Last Modified: 31 Jan 2013 01:04
URI: https://oak.novartis.com/id/eprint/866

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