HDAC Inhibitors as Epigenetic Regulators

All types of APCs can provide signal one, but only professional APCs, with dendritic cells (DCs) being the most potent type, can provide both signals. subsets of blood DCs, myeloid and plasmacytoid (mDCs and pDCs, respectively). The comparative analyses of results demonstrated a decreased pDC frequency in both ATL and HAM/TSP patients as compared to ACs and seronegative controls. Similarly, CD86 expression on both mDCs and pDCs was significantly higher in HAM/TSP (but not ATL) patients compared to ACs. Interestingly, HLA-DR expression was significantly lower Cefamandole nafate Cefamandole nafate on Cefamandole nafate pDCs of patients as compared to service providers; however, for mDCs, only the HAM/TSP group experienced significantly lower expression of HLA-DR. Unlike HAM/TSP individuals, ATL individuals experienced higher HLA-ABC expression on mDCs compared to ACs. Finally, both mDCs and pDCs of HAM/TSP patients had significantly higher expression of the programmed death ligand 1 (PD-L1) compared to ACs. Overall, this study suggests that DCs exhibit a differential phenotypic and functional profile between patients (ATL and HAM/TSP) and service providers of HTLV-1 and could provide an important tool for understanding HTLV-1 immunopathogenesis during contamination and disease. Introduction Human T cell leukemia computer virus type 1 (HTLV-1) is an exogenous retrovirus that infects approximately 15C20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa.1C3 The virus spreads through contact with bodily fluids containing infected cells most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3C5% of HTLV-1-infected individuals develop either adult T cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). ATL is usually marked by phenotypic as well as functional abnormalities in CD4+ T cells that ultimately result in severe immunodeficiency. On the other hand, HAM/TSP is characterized by infiltration of mononuclear cells into the central nervous system followed by demyelination and axonal destruction ultimately leading to chronic inflammation. It is not clear Cefamandole nafate why only a small percentage of HTLV-1-infected individuals develop these diseases. Also, the sequence and` nature of events that contribute to ATL and HAM/TSP are not completely understood and this is the reason why clinical management of both these diseases has been unsatisfactory. Activation of naive T cells requires the formation of close physical contact (termed as immunological synapse) between a T cell and an antigen-presenting cell (APC). APCs provide two kinds of signals: signal one (antigen presentation) and signal two (costimulation). All types of APCs can provide signal one, but only professional APCs, with dendritic cells (DCs) being the most potent type, can provide both signals. Therefore, DCs play a crucial role in initiating and regulating a potent antiviral T cell response and many viruses are known to modulate DC functions in order to cause productive infection within their host. With respect to their role in HTLV-1 immunopathogenesis, DCs from HAM/TSP patients were found Cefamandole nafate to be infected with HTLV-1 and capable of stimulating autologous lymphocyte proliferation.4 We5,6 and others7 have also demonstrated that DCs can become infected with HTLV-1 phenotypic characterization and functional characterization of DCs pose a problem due to the low frequency of these cells in the peripheral blood (0.4% and 0.2% for mDCs and pDCs, respectively) and the multiple markers needed to identify specific DC subsets. Spry2 Polychromatic flow cytometry is a useful technique for circumventing this problem that offers high sensitivity and greater statistical power. Few reports have demonstrated the use of polychromatic flow cytometry for the characterization of DCs in both blood and peripheral blood mononuclear cells (PBMCs).14C16 While useful, these assays present some limitations including lack of phenotypic/functional characterization and/or inclusion of cumbersome multistep staining with unconjugated and secondary antibodies. Thus, the need still exists for more detailed functional phenotyping of circulating human DC subsets. In this respect, we have developed and standardized a human DC 13-color flow cytometry antibody cocktail to perform extensive DC phenotyping within the context of total PBMCs. Once optimized, we used this cocktail to characterize mDCs and pDCs among asymptomatic carriers (ACs), ATL, and HAM/TSP individuals in a patient cohort from the endemic region of Jamaica. Besides.