Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses

K Nündel, NM Green, AL Shaffer, KL Moody… - The Journal of …, 2015 - journals.aai.org
K Nündel, NM Green, AL Shaffer, KL Moody, P Busto, D Eilat, K Miyake, MA Oropallo…
The Journal of Immunology, 2015journals.aai.org
Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic
erythematosus lupus, in which DNA-and RNA-associated autoantigens activate autoreactive
B cells through TLR9-and TLR7-dependent pathways. Nevertheless, TLR9-deficient
autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and
TLR7/9–double deficient autoimmune-prone mice develop less severe disease. To
determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the …
Abstract
Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic erythematosus lupus, in which DNA-and RNA-associated autoantigens activate autoreactive B cells through TLR9-and TLR7-dependent pathways. Nevertheless, TLR9-deficient autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and TLR7/9–double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the functional properties of autoantigen-activated wild-type, TLR9-deficient, and TLR7-deficient B cells in an experimental system in which proliferation depends on BCR/TLR coengagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than are either wild-type or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody-producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus.
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