Plexin-A4 negatively regulates T lymphocyte responses.
Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also in the regulation of immune responses. Plexin-A4, a member of the plexin-A subfamily, forms a receptor complex with neuropilins and transduces signals for class III semaphorins in the nervous system. Although plexin-A4 is also expressed in the lymphoid tissues, the involvement of plexin-A4 in immune responses remains unknown. To explore the role of plexin-A4 in the immune system, we analyzed immune responses in plexin-A4-deficient (plexin-A4-/-) mice. Among immune cells, plexin-A4 mRNA was detected in T cells, dendritic cells and macrophages but not in B cells and NK cells. Plexin-A4-/- mice had normal numbers and cell surface markers for each lymphocyte subset, suggesting that plexin-A4 is not essential for lymphocyte development. However, plexin-A4-/- mice exhibited enhanced antigen-specific T cell responses and heightened sensitivity to experimental autoimmune encephalomyelitis. Plexin-A4-/- T cells exhibited hyperproliferative responses to anti-CD3 stimulation and to allogeneic dendritic cells in vitro. Furthermore, this hyperproliferation was also observed in both T cells from neuropilin-1 mutant (npn-1(Sema-)) mice, in which the binding site of class III semaphorins is disrupted, and T cells from Sema3A-deficient (Sema-3A-/-) mice. Collectively, these results suggest that plexin-A4, as a component of the receptor complex for class III semaphorins, negatively regulates T cell-mediated immune responses.
Yamamoto
Midori
M
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Suzuki
Kazuhiro
K
Okuno
Tatsusada
T
Ogata
Takehiro
T
Takegahara
Noriko
N
Takamatsu
Hyota
H
Mizui
Masayuki
M
Taniguchi
Masahiko
M
Chédotal
Alain
A
Suto
Fumikazu
F
Fujisawa
Hajime
H
Kumanogoh
Atsushi
A
Kikutani
Hitoshi
H
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D039961:Semaphorins / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D008024:Ligands; D009419:Nerve Tissue Proteins; C492110:Plxna4 protein, mouse; D011956:Receptors, Cell Surface; D039961:Semaphorins