Detailed Description
The Pdcd1lg2 gene encodes the costimulatory molecule PD-L2 which is expressed in dendritic cells (DCs). To establish the mouse line Stk 017515 - B6N.129(Cg)-Pdcd1lg2tm2Dmp/J which is deficient for PD-L2, a genomic fragment containing exon 2 of the programmed cell death 1 ligand 2 (Pdcd1lg2 which encodes PD-L2) gene, two of loxP sites and one of EGFP site were incorporated to inactivate PD-L2 expression. Offspring were backcrossed with BALB/c more than nine generations and typed as PD-L2 wild type (WT) and knockout (KO) by Southern blot and PCR. PD-L2 expression was completely abolished on bone marrow derived, and splenic dendritic cells. Homozygotes are viable and fertile.
PD-L2 binds to the PD-1 immunoreceptor tyrosine-based inhibitory motif-containing receptor expressed on activated T cells where it regulates self- tolerance and immune responses to microbes. PD-L2 also binds repulsive guidance molecule b (RGMb) which is expressed by normal resting lung interstitial macrophages and alveolar epithelial cells.
The PD-L2 KO mice exhibit a reduction of intrahepatic tumor-specific CD8 T cells, interferon-γ (IFN-γ) production by CD4 T cells, IFN-γ-dependent humoral responses , antigen-specific CD8 T cell responses, and cytotoxic T lymphocyte (CTL) activity. In these mice hepatic tumors grow more quickly than in wildtype mice. Experiments with PD-L2-deficient mice showed that PD-L2 expression on non-T cells was critical for respiratory tolerance, but expression on T cells was not required.
Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders.
These mice may be useful for studying self-tolerance, Th1 and Th2 immune responses.
Publication:
Shin T; Yoshimura K; Shin T; Crafton EB; Tsuchiya H; Housseau F; Koseki H; Schulick RD; Chen L; Pardoll DM. 2005. In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses. J Exp Med 201(10):1531-41
