TRAF1 in Human Health and Disease

TRAF1 is a signaling adaptor known for its role in tumour necrosis factor receptor (TNFR)-induced cell survival. This thesis explores the role of TRAF1 in human health and several disease states, including autoimmunity, infectious disease and cancer. Genome wide association studies identified an association between single nucleotide polymorphisms (SNPs) in the TRAF1 gene with increased incidence of rheumatoid arthritis (RA) and other autoimmune diseases. I provide a compelling explanation for how this SNP could contribute to the increased incidence and severity of RA and other inflammatory diseases by presenting evidence that healthy donors with the RA-associated SNP express less TRAF1 protein but higher levels of inflammatory cytokines due to an unexpected role for TRAF1 in negatively-regulating TLR signaling. In the context of infectious disease, it had been shown that the loss of TRAF1 from chronically stimulated CD8 T cells results in desensitization of the 4-1BB signaling pathway, thereby contributing to T cell exhaustion during chronic infection. Previous results showed that IL-7 can restore TRAF1 expression in virus specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. I show that IL-7 therapy in antiretroviral therapy treated patients induces sustained changes in the number and phenotype of HIV-specific T cells, including increased levels of phospho-ribosomal protein S6 and increased frequency of TRAF1+ cells. TNFR family members such as CD40 play important roles in driving NF-B activation in B cell related cancers, including chronic lymphocytic leukemia (CLL). Here I present evidence that the protein kinase C related kinase, PKN1, is required to protect the pro-survival signaling adaptor TRAF1 from degradation during constitutive CD40 signaling. Accordingly, treatment of patient CLL cells with a PKN1 inhibitor lowered TRAF1 and other survival molecules and resulted in increased cell death. These findings provide proof of concept for PKN1 as a novel target for killing CLL cells. Altogether, these studies have advanced our understanding of the impact of TRAF1 in human disease as an important molecule that can limit inflammation and contribute to control of chronic viral infection. My findings also identify TRAF1 as a potential biomarker and may inform the development of a novel therapy for human B cell malignancies.Ph.D