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- Title
Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure.
- Authors
Barbara Metzler; Patrick Gfeller; Grazyna Wieczorek; Jianping Li; Barbara Nuesslein-Hildesheim; Andreas Katopodis; Matthias Mueller; Volker Brinkmann
- 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 (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 IFNγ-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.
- Subjects
T cells; HOMEOSTASIS; GENOTYPE-environment interaction; LYMPH nodes
- Publication
International Immunology, 2008, Vol 20, Issue 5, p633
- ISSN
0953-8178
- Publication type
Article
- DOI
10.1093/intimm/dxn023