Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection
Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar
Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar
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Research Article AIDS/HIV

Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection

Abstract

Although antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the SIV model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression and determined associated molecular/metabolic signatures. MSC administration to SIV-infected macaques resulted in viral reduction and heightened virus-specific responses. Marked clearance of SIV-positive cells from gut mucosal effector sites was correlated with robust regeneration of germinal centers, restoration of follicular B cells and T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within the follicular DC network. Gut transcriptomic analyses showed increased antiviral response mediated by pathways of type I/II IFN signaling, viral restriction factors, innate immunity, and B cell proliferation and provided the molecular signature underlying enhanced host immunity. Metabolic analysis revealed strong correlations between B and Tfh cell activation, anti-SIV antibodies, and IL-7 expression with enriched retinol metabolism, which facilitates gut homing of antigen-activated lymphocytes. We identified potentially new MSC functions in modulating antiviral immunity for enhanced viral clearance predominantly through type I/II IFN signaling and B cell signature, providing a road map for multipronged HIV eradication strategies.

Authors

Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar

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Figure 3

MSC administration leads to a robust germinal center and Tfh response in the gut-associated lymphoid tissue and periphery.

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MSC administration leads to a robust germinal center and Tfh response in...
(A) IHC analysis of cells expressing PD-1+, CD3+, and CD20+ within ileal lymphoid follicles from representative SIV–, SIV+, and SIV+MSC+ macaques. Gut sections show nuclei (blue), anti-CD20 (white), anti–PD-1 (red), and anti-CD3 (green) stains to highlight PD-1 expression on CD3-expressing cells in the lymphoid follicle. Magnification 20×. Scale bars: 50 μm. (B) Quantification of CD3+ PD-1+ cells per follicle. (C) Representative images of MsLN follicles of SIV+ and SIV+MSC+ animals. Magnification 20×. Scale bars: 50 μm. (D) Gating strategy for identification of Tfh cells and GC B cells. Cells were previously gated on lymphocytes, singlets, and live cells. (E and F) Percentage of Tfh (CD4+ CXCR5+) and GC B cells in MsLNs (SIV– n = 5, SIV+ n = 7, and SIV+MSC+ n = 5). (G–J) Heatmaps display differential expression of genes associated with Tfh activation, GC formation, B cell proliferation, and antigen presentation. Significant (*FDR < 0.1) and trending (Δ P < 0.05) genes annotated. Data represent the mean (± SEM) for each time point. Significance was determined using 1-way ANOVA with Holm-Sidak post hoc testing for multiple comparisons (C, D, and F) or Spearman’s rank correlation with linear regression (E). *P < 0.05 and **P ≤ 0.01.