Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation
Josephine R. Giles, Adriana Turqueti Neves, Ann Marshak-Rothstein, Mark J. Shlomchik
Josephine R. Giles, Adriana Turqueti Neves, Ann Marshak-Rothstein, Mark J. Shlomchik
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Research Article Immunology

Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

Abstract

T cells play a significant role in the pathogenesis of systemic autoimmune diseases, including systemic lupus erythematosus; however, there is relatively little information on the nature and specificity of autoreactive T cells. Identifying such cells has been technically difficult because they are likely to be rare and low affinity. Here, we report a method for identifying autoreactive T cell clones that recognize proteins contained in autoantibody immune complexes, providing direct evidence that functional autoreactive helper T cells exist in the periphery of normal mice. These T cells significantly enhanced autoreactive B cell proliferation and altered B cell differentiation in vivo. Most importantly, these autoreactive T cells were able to rescue many aspects of the TLR-deficient AM14 (anti-IgG2a rheumatoid factor) B cell response, suggesting that TLR requirements can be bypassed. This result has implications for the efficacy of TLR-targeted therapy in the treatment of ongoing disease.

Authors

Josephine R. Giles, Adriana Turqueti Neves, Ann Marshak-Rothstein, Mark J. Shlomchik

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Figure 5

13C2 T cells can adopt a Tfh cell phenotype and induce AM14 B cells to differentiate into germinal center cells.

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13C2 T cells can adopt a Tfh cell phenotype and induce AM14 B cells to d...
(A) Representative flow cytometry plots from the experiment described in Figure 4; percentages reflect the mean. Cells were first gated as live and 4-44+. (B and C) Experimental design is as depicted in Figure 4A, except 5 × 106 AM14 B cells and 2.5 × 105 T cells were transferred. (B) Representative flow cytometry histograms of PBs (CD138+CD44+intracellular 4-44hi) and germinal center (GC) cells (CD38loCD95+) from mice that received AM14 B cells and PL2-3, without or with 13C2 T cells. Percentages reflect means from 4 experiments, with 14 and 16 total mice per group, respectively. (C) Representative flow cytometry plots and histograms gated on Rg T cells from mice that received AM14 B cells and 13C2 T cells, without and with PL2-3. Percentages reflect means from 6 experiments, with 8 and 25 total mice per group, respectively. All cells were first gated as live. (D–G) Immunofluorescent histology from the experiment described in Figure 4; representative of 2 similar experiments. (D and F) Representative images from mice that received AM14 B cells and PL2-3. (E and G) Representative images from mice that received AM14 B cells, 13C2 T cells, and PL2-3. Each column of images is from a different mouse. White arrows indicate 4-44+ PNA+ GC cells. Original magnification, ×20. Scale bar: 100 μm.