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 5

Progressively altered T cell positioning limits CD4+ T cell activation.

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Progressively altered T cell positioning limits CD4+ T cell activation. ...
(A) Experimental design. (B) Expression of activation markers on GFP+ transgenic (Tg) cells at weeks 3 and 8 p.i. (C) Percentage of CD69+ Tg cells in the mLN and spleen. (D) Left: Representative image of M. tuberculosis bacteria (arrowheads) and CD11b+ cells. Right: Images with enlarged view showing p-S6+ and p-S6– GFP+ cells. Scale bars: 50 μm and 10 μm (inset). White line: foci border. (E) Proportion of p-S6+ Tg cells in whole mLN section (left) and within M. tuberculosis+CD11b+ foci (right). (F) Image of paracortical B cell cluster and position of E6 Tg cells and M. tuberculosis foci (arrowhead). Scale bar: 50 μm. (G) Percentages of Tg cells localized inside or outside of paracortical B cell clusters. (H) IFR in mLNs of naive and 8-week M. tuberculosis–infected mice (enlarged regional view of mLNs from Figure 2A). Dashed lines delineate the B cell follicles. Scale bars: 50 μm. Arrowheads indicate the IFR in mLN section of naive mice. Right: Diagrams of LN compartments in naive (top) and M. tuberculosis–infected (bottom) mLN. (I) Left: Images of mLN showing location of Tg cells (pseudocolored). Scale bars: 200 μm. Right: Quantification of Tg cells in the subcompartments of the mLN as defined in H. (J) Preference index indicating localization preference of total Tg (left) or p-S6+ Tg cells (right) in infected mLN. (K) Percentages of T-bet+ and CXCR3+ in Tg cells. Data in B, C, E, G, and I–K are from 2 independent experiments (6–8 mice per group in total), and images in D, F, and H are representatives from 2 independent experiments with similar results (3–5 mice per group in total). **P < 0.01, ***P < 0.001, ****P < 0.0001 by Student’s t test (C, E, G, J, and K) or 1-way ANOVA with Tukey’s multiple-comparison test (I).