Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both alphabeta and gammadelta T cells but does not require MyD88 signaling.
Vaccination of nonautoimmune prone mice with syngeneic dendritic cells (DC) readily induces anti-DNA autoantibodies but does not trigger systemic disease. We observed that anti-DNA autoantibody generation absolutely required alphabeta T cells and that gammadelta T cells also contributed to the response, but that regulatory T cells restrained autoantibody production. Although both NZB/W F(1) mice and DC vaccinated C57/BL6 mice produced autoantibodies against dsDNA, vaccinated mice had higher levels of Abs against H1 histone and lower levels of antinucleosome Abs than NZB/W F(1) mice. Despite a 100-fold increase in IL-12 and Th1 skewing to a foreign Ag, OVA, synergistic TLR activation of DC in vitro failed to augment anti-DNA Abs or promote class switching beyond that induced by LPS alone. TLR stimulation was not absolutely required for the initial loss of B cell tolerance because anti-DNA levels were similar when wild-type (WT) or MyD88-deficient DC were used for vaccination or WT and MyD88-deficient recipients were vaccinated with WT DC. In contrast, systemic administration of LPS, augmented anti-DNA Ab levels and promoted class switching, and this response was dependent on donor DC signaling via MyD88. LPS also augmented responses in the MyD88-deficient recipients, suggesting that LPS likely exerts its effects on both transferred DC and host B cells in vivo. These results indicate that both the alphabeta and gammadelta subsets are necessary for promoting autoantibody production by DC vaccination, and that although TLR/MyD88 signaling is not absolutely required for initiation, this pathway does promote augmentation, and Th1-mediated skewing, of anti-DNA autoantibodies.
Martin
David A
DA
Division of Rheumatology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Zhang
Kang
K
Kenkel
Justin
J
Hughes
Grant
G
Clark
Edward
E
Davidson
Anne
A
Elkon
Keith B
KB
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002470:Cell Survival; D002843:Chromatin / Q000276:immunology; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D002843:Chromatin; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D051193:Toll-Like Receptors; D004247:DNA