Co-expression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
Posted by rob on March 13, 2011 under Uncategorized | 
Comments are off for this article
Co-expression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
Blood. 2011 Mar 8;
Authors: Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, Blazar BR
Tumor-associated immune suppression can lead to defective T cell-mediated anti-tumor immunity. Here we identified a unique phenotype of exhausted T-cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the co-expression of Tim-3 and PD-1 on CD8+T-cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 co-expression increased during AML progression. PD-1+Tim-3+ CD8+T-cells were deficient in their ability to produce IFN-?, TNF-?, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, upregulated Tim-3 during AML progression and such Tim-3+PD-1- KO CD8+T-cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced Tregulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8+T-cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing albeit not eliminating both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8+T-cell exhaustion in patients with hematological malignancies such as advanced AML.
PMID: 21385853 [PubMed - as supplied by publisher]