Autoreactive preplasma cells break tolerance in the absence of regulation by dendritic cells and macrophages.
The ability to induce Ab responses to pathogens while maintaining the quiescence of autoreactive cells is an important aspect of immune tolerance. During activation of TLR4, dendritic cells (DCs) and macrophages (MFs) repress autoantibody production through their secretion of IL-6 and soluble CD40L (sCD40L). These soluble mediators selectively repress B cells chronically exposed to Ag, but not naive cells, suggesting a means to maintain tolerance during TLR4 stimulation, yet allow immunity. In this study, we identify TNF-α as a third repressive factor, which together with IL-6 and CD40L account for nearly all the repression conferred by DCs and MFs. Similar to IL-6 and sCD40L, TNF-α did not alter B cell proliferation or survival. Instead, it reduced the number of Ab-secreting cells. To address whether the soluble mediators secreted by DCs and MFs functioned in vivo, we generated mice lacking IL-6, CD40L, and TNF-α. Compared to wild-type mice, these mice showed prolonged anti-nuclear Ab responses following TLR4 stimulation. Furthermore, adoptive transfer of autoreactive B cells into chimeric IL-6(-/-) × CD40L(-/-) × TNF-α(-/-) mice showed that preplasma cells secreted autoantibodies independent of germinal center formation or extrafollicular foci. These data indicate that in the absence of genetic predisposition to autoimmunity, loss of endogenous IL-6, CD40L, and TNF-α promotes autoantibody secretion during TLR4 stimulation.
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Mileka R
MR
Gilbert
Nikki J
NJ
Wagner
Shannon Z
SZ
Jones
Amanda B
AB
Wisz
Jose R
JR
Roques
Kristen N
KN
Krum
Sang-Ryul
SR
Lee
Volker
V
Nickeleit
Chrys
C
Hulbert
James W
JW
Thomas
Stephen B
SB
Gauld
Barbara J
BJ
Vilen
D019264:Adoptive Transfer; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000172:deficiency; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D015850:Interleukin-6 / Q000172:deficiency; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D011828:Radiation Chimera / Q000276:immunology; D013234:Stem Cells / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency
D034961:Antigens, Nuclear; D001323:Autoantibodies; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand