6 research outputs found
Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response
Lung cancer is the leading cause of cancer-related mortality in the world, resulting in over a million deaths each year. Non-small cell lung cancers (NSCLCs) are characterized by a poor immunogenic response, which may be the result of immunosuppressive factors such as prostaglandin E2 (PGE2) present in the tumor environment. The effect of PGE2 in the suppression of anti-tumor immunity and its promotion of tumor survival has been established for over three decades, but with limited mechanistic understanding. We have previously reported that PGE2 activates hematopoietic progenitor kinase 1 (HPK1), a hematopoietic-specific kinase known to negatively regulate T-cell receptor signaling. Here, we report that mice genetically lacking HPK1 resist the growth of PGE2-producing Lewis lung carcinoma (LLC). The presence of tumor-infiltrating lymphocytes (TILs) and T-cell transfer into T cell-deficient mice revealed that tumor rejection is T cell mediated. Further analysis demonstrated that this may be significantly due to the ability of HPK1−/− T cells to withstand PGE2-mediated suppression of T-cell proliferation, IL-2 production, and apoptosis. We conclude that PGE2 utilizes HPK1 to suppress T cell-mediated anti-tumor responses
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The rabbit model for HTLV-I infection
Rabbit HTLV-I transformed cell lines possessing diverse biological properties were derived in vitro from peripheral blood lymphocytes of New Zealand White rabbits. Two of the cell lines caused fatal leukemia with infiltration in the lungs, spleen, liver and kidneys of adult rabbit recipients within 10 days of inoculation. To determine whether cell lineage influences pathogenesis, the fatal leukemogenic cell lines were compared to those that cause benign chronic infection. Selected rabbit genes including TCR , TCR , IL-2R and CD8 were cloned for use as probes for characterization of the lines. Although rabbit CD4+ and CD8+ T cells can be infected by HTLV-I, CD4-CD8- T cells predominated in our collection. Even though, the two HTLV-I lines with a leukemogenic effect were T cells, their lethal nature cannot be attributed solely to their lineage since other T cells failed to exhibit the same property. The dominance of HTLV-I T cell lines may be attributable to the high number of T cells in the rabbit peripheral blood. Since T cells predominate in rabbit HTLV-I infection, the primary structures of the rabbit TCR and cDNA clones were determined. Exons 1 and 3 of both TCR and shared a high degree of identity with their counterparts in other species. By contrast, exon 2 structures of both TCR and TCR chains were highly divergent among species. Rabbit C and C exon 2 lack a conserved cysteine residue thought to be responsible for disulfide bond between the TCR and TCR chain. Two allelic forms of rabbit C were found. One allele has two copies of exon 2 arranged tandemly in the same orientation. Genomic sequence analysis revealed a 464 base pair insertion between C exons 1 and 3. The presence of a duplicate C exon 2 has not been reported for any other species. Availability of these cloned genes provides the groundwork for development of reagents specific for rabbit T cells