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Brugia malayi Microfilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4⁺ T Cells

Roshanak Tolouei Semnani^1,*, Anne Y. Liu^*,, Helen Sabzevari, Joseph Kubofcik^*, Jun Zhou, Julia K. Gilden^* and Thomas B. Nutman^*

^* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Howard Hughes Medical Institute, Research Scholars Program, and Laboratory of Tumor Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Parasite Ag-specific T cell unresponsiveness and diminished IFN- production are immunologic hallmarks of patent infection with lymph-dwelling filarial nematodes. Although this diminished responsiveness is directed primarily against the intravascular microfilarial (MF) parasite stage and mediated in part by reduced APC function, the mechanisms involved are not fully understood. In this report, we demonstrate that human dendritic cells (DC) exposed to live MF up-regulate both the cell surface and gene expression of CD54 (ICAM-1). Moreover, live MF result in a 3-fold increase in DC death compared with MF-unexposed DC, primarily due to apoptosis. Notably, microarray and real-time RT-PCR data indicate that live MF concurrently up-regulate mRNA expression of proinflammatory molecules such as IL-8, RANTES, IL-1, TNF-, and IL- in DC, the presence of which is also detected at the protein level, while inhibiting the production of IL-12 (p40 and p70) and IL-10. Soluble excretory-secretory products from live MF diminished IL-12 and IL-10 production and induced DC death, although to a lesser degree. Moreover, exposure of DC to live MF resulted in a decrease in the ability of DC to promote CD4⁺ T cell production of IFN- and IL-5. Our findings clearly suggest that the interaction between live MF and DC is complex but contributes to the hyporesponsiveness and parasite persistence associated with the MF⁺ state in the infected human. These data further suggest that MF induce an orchestrated response in APC that leads to a diminished capacity to function appropriately, which in turn has significant consequences for CD4⁺ T cells.

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