Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis–infected mice
Lina Daniel, … , Warwick J. Britton, Carl G. Feng
Lina Daniel, … , Warwick J. Britton, Carl G. Feng
Published November 1, 2022
Citation Information: J Clin Invest. 2022;132(21):e157873. https://doi.org/10.1172/JCI157873.
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Research Article Immunology Infectious disease

Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis–infected mice

Abstract

An effective adaptive immune response depends on the organized architecture of secondary lymphoid organs, including the lymph nodes (LNs). While the cellular composition and microanatomy of LNs under steady state are well defined, the impact of chronic tissue inflammation on the structure and function of draining LNs is incompletely understood. Here we showed that Mycobacterium tuberculosis infection remodeled LN architecture by increasing the number and paracortical translocation of B cells. The formation of paracortical B lymphocyte and CD35+ follicular dendritic cell clusters dispersed CCL21-producing fibroblastic reticular cells and segregated pathogen-containing myeloid cells from antigen-specific CD4+ T cells. Depletion of B cells restored the chemokine and lymphoid structure and reduced bacterial burdens in LNs of the chronically infected mice. Importantly, this remodeling process impaired activation of naive CD4+ T cells in response to mycobacterial and unrelated antigens during chronic tuberculosis infection. Our studies reveal a mechanism in the regulation of LN microanatomy during inflammation and identify B cells as a critical element limiting the T cell response to persistent intracellular infection in LNs.

Authors

Lina Daniel, Nayan D. Bhattacharyya, Claudio Counoupas, Yi Cai, Xinchun Chen, James A. Triccas, Warwick J. Britton, Carl G. Feng

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Figure 3

B cell depletion restores T cell organization and reduces M. tuberculosis loads in mLN.

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B cell depletion restores T cell organization and reduces M. tuberculosi...
(A and B) Summary flow cytometry data of mLN from anti-CD4 mAb–treated B6 WT mice at week 8 p.i. (A) Percentages and numbers of B220+ cells. (B) Ratio of B220+ cells to CD8+ T cells. (C) Proportion and numbers of B cells (B220+) in the mLN of week-3 M. tuberculosis–infected WT, Tnfr1–/–, Ifnar1–/–, and Ifngr1–/– mice. (D) Representative images of CCL21- and CD3-costained mLN from isotype control or anti-CD20 mAb–treated M. tuberculosis–infected mice. Scale bars: 300 μm. (E) Histograms representing the average fluorescence intensity of CCL21 and CD3 along the cortex-medullary axis of isotype control and anti-CD20–treated mice. Arrowheads represent paracortical region occupied by B cell clusters in control mice. (F) Bacterial loads in the mLN of control and anti-CD20 mAb–treated mice measured at weeks 3 and 16 p.i. (G) The total number of cells in the mLN of isotype control and anti-CD20–treated mice at week 16 p.i. (H) Ratio of CD4+ to CD8+ T cells (left) and total number of CD4+ T cells (right) in the mLN of isotype control and anti-CD20–treated mice at week 16 p.i. (I) MFI of expression in ESAT-64–17–specific CD4+ T cells in the mLN at week 16 p.i. Data in A–E are representative 2 independent experiments (n = 6–8 mice per group). Data in F–I are representative of 3 independent experiments with similar results (n = 6 mice per group). Statistical differences between groups were determined using Student’s t test (A, B, and F–I) or 1-way ANOVA with Tukey’s multiple-comparison test (C). *P < 0.05, **P < 0.01, ***P < 0.001.