Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure.
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Metzler, Barbara, Gfeller, Patrick, Wieczorek, Grazyna, Li, Jianping, Nuesslein-Hildesheim, Barbara, Katopodis, Andreas, 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 |