ABSTRACT
gammadelta T cells participate in the innate immune response to a variety of infectious microorganisms. They also link to the adaptive immune response through their induction of maturation of dendritic cells (DC) during the early phase of an immune response when the frequency of Ag-specific T cells is very low. We observe that in the presence of Borrelia burgdorferi, synovial Vdelta1 T cells from Lyme arthritis synovial fluid potently induce maturation of DC, including production of IL-12, and increased surface expression of CD40 and CD86. The activated DC are then able to stimulate the Vdelta1 T cells to up-regulate CD25. Both of these processes are initiated primarily by Fas stimulation rather than CD40 activation of DC via high expression of Fas ligand by the Vdelta1 T cells. DC are resistant to Fas-induced death due to expression of high levels of the Fas inhibitor c-FLIP. This effect serves to divert Fas-mediated signals from the caspase cascade to the ERK MAPK and NF-kappaB pathways. The findings affirm the importance of the interaction of certain T cell populations with DC during the early phases of the innate immune response. They also underscore the view that as levels of c-FLIP increase, Fas signaling can be diverted from induction of apoptosis to pathways leading to cell effector function.
Subject(s)
Dendritic Cells/physiology , Lyme Disease/immunology , Membrane Glycoproteins/physiology , Receptors, Antigen, T-Cell, gamma-delta/physiology , Synovial Fluid/immunology , T-Lymphocytes/physiology , Tumor Necrosis Factors/physiology , CASP8 and FADD-Like Apoptosis Regulating Protein , CD40 Ligand/analysis , Extracellular Signal-Regulated MAP Kinases/metabolism , Fas Ligand Protein , Humans , Interleukin-12/biosynthesis , Intracellular Signaling Peptides and Proteins/analysis , NF-kappa B/metabolism , Receptors, Interleukin-2/analysisABSTRACT
Gamma delta T cells accumulate at epithelial barriers and at sites of inflammation in various infectious and autoimmune diseases, yet little is understood about the function of tissue-infiltrating gamma delta T cells. We observe that gamma delta T cells of the V delta 1 subset accumulate in synovial fluid of human Lyme arthritis and are intensely cytolytic toward a wide array of target cells. Particularly striking is that the cytolytic activity is highly prolonged, lasting for at least 3 wk after stimulation of the gamma delta T cells with Borrelia burgdorferi. Cytolysis is largely Fas dependent and results from very high and prolonged expression of surface Fas ligand, which is transcriptionally regulated. This also manifests in a substantial level of self-induced apoptosis of the gamma delta T cells. In this capacity, certain gamma delta T cell subsets may serve as cytolytic sentinels at sites of inflammation, and perhaps at epithelial barriers.
