Endothelial basement membrane laminin a5 selectively inhibits T lymphocyte extravasation into the brain

Wu C et al. Nat. Med. 15, 519-527, 2009

Speaker: Wen-Hsin Yao (姚文欣)                                 Time: 14:00~15:00, Oct. 21, 2009

Commentator: Dr. Huan-Yao Lei (黎煥耀 教授)        Place: Room 601

Abstract:

During inflammation, leucocytes transmigrate from blood vessels to inflamed site, and the processes leucocytes transmigration through vascular endothelial cell are well studied. However, the contribution of underlying basement membrane (BM) to leucocytes penetration is still unclear. BMs are composed of laminins (Lm), collegens, nidogens and heparin sulfate. In the previous study, the authors found that with high level of Lm 8 (a4b1g1) are permissive for T cell transmigration, whereas Lm 10 (a5b1g1) are restrictive¹. To investigate the role of Lms on T cell transmigration, experimental autoimmune encephalomyelitis (EAE) of Lm a4-deficient (Lama4^-/-) mice were used. Lama4^-/- mice show a compensatory Lm a5 expression and had no changes on blood vessels morphology or other BM components and junctional proteins. When EAE was induced, Lama4^-/- mice showed lower disease severity compare to wild type (wt) mice. This may attribute to a decrease in the number of disease-inducing CD4+ T cells infiltrating into the brain. As Lm a4 and a5 serve as cofactor for T cell activation^2,3, the authors further used a passive EAE model to ruled out the possibility that non-functional T cells on Lama4^-/- mice lead to lower disease severity. Further, the number of passively transferred MOG_35-55-specific T cells in Lama4^-/- mice brain were lower than those in wt mice suggesting a defect in T cell migrating through CNS venules. Finally, the authors found that T cells migrating though Lm a4 was integrin a6b1-mediated and Lm a5 actively inhibited such action. In conclusion, Lm a5 inhibits integrin a6b1-mediated T cell transmigration on Lm a4-rich BM, and this observation may offer a new therapeutic way for neuroinflammatory diseases.

References

1.      Sixt, M. et al. Endothelial cell laminin isoforms, laminin 8 and 10, play decisive roles in in T-cell recruitment across the blood-brain-barrier in an experimental autoimmune encephalitis model (EAE). J. Cell Biol. 153, 933–946 (2001)

2.      Geberhiwot, T. et al. Laminin-8 (a4b1g1) is synthesized by lymphoid cells, promotes lymphocyte migration and costimulates T cell proliferation. J. Cell Sci. 114, 423–433 (2001).

3.      Gorfu, G. et al. Laminin isoforms of lymph nodes and predominant role of a5-laminin(s) in adhesion and migration of blood lymphocytes. J. Leukoc. Biol. 84, 701–712 (2008).