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Meher Y. Patel
Molecular Pathology and Immunology Program
M.S. 2009, William Paterson University, New Jersey
B.S. 2006, Houston Baptist University, Texas
B.S. 2002, University of Pune, India
Thesis Advisor: Patricia Fitzgerald-Bocarsly, Ph.D.
Department of Pathology and Laboratory Medicine
Thursday, October 22, 2015
12:00 P.M., MSB C-600
Although plasmacytoid dendritic cells (pDC) constitute a minor fraction of the total human peripheral blood mononuclear cell population, they are crucial contributors to the innate as well as adaptive immune responses. Upon encounter with virus, pDC become activated and produce copious amounts of Interferon-ƒÑ and pro-inflammatory cytokines. Aberrant immune activation and immune exhaustion along with CD4 T cell depletion and uncontrolled viremia are characteristic features of chronic HIV infection. Persistent immune activation contributes to HIV disease progression and enhances the risk of non-AIDS related co-morbidities. In chronic HIV infection, pDC can contribute to disease pathogenesis through their immunosuppressive and inflammatory functions as well as through their depletion. Elevated plasma LPS resulting from microbial translocation is a major factor contributing to HIV-associated immune activation. We found that viremic HIV-infected individuals have higher expression of the LPS receptor, TLR4, on their pDC compared to healthy subjects. However, how TLR4 signaling affects pDC activation and function in the context of HIV infection has not been investigated before. We co-stimulated pDC with LPS and HIV and discovered that TLR4 signaling potentiated HIV-induced pDC activation and PD-L1 expression and PD-L1 was co-expressed preferentially on activated pDC. We also found that HIV-infected individuals had enhanced PD-L1 expression and specifically their TLR4-positive pDC had higher PD-L1 expression compared to healthy subjects. We examined the effect of LPS and HIV co-stimulation on pDC capacity to induce T cell proliferation and found that co-stimulated pDC repressed T cell proliferation. LPS and HIV co-stimulation also enhanced the capacity of pDC for migration and the majority of migrated pDC were PD-L1-positive. Together, these results suggest that in the setting of HIV infection enhancement of pDC immune suppressive mechanisms such as PD-L1 are an outcome of HIV-associated immune activation potentiated by TLR4 signaling.