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
View: Text | PDF
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

×

Figure 5

MSC promotes greater T cell proliferation and specific response to virus.

Options: View larger image (or click on image) Download as PowerPoint
MSC promotes greater T cell proliferation and specific response to virus...
(A and B) Percentages of proliferating Ki67+ CD8+ cells were determined by flow cytometry in the gut (SIV– n = 3, SIV+ n = 5, and SIV+MSC+ n = 5) and periphery (SIV+ n = 7, SIV+MSC+ n = 5) at 70 days after infection and longitudinally, respectively. (C) Spearman’s correlation between proliferating CD8+ T cells and viral loads. Linear regression coefficients and P values are shown. (D) SIV-specific cellular response. Intracellular expression of IFN-γ in SIV-gag peptide–stimulated CD8+ (P = 0.29, NS) T cells (SIV+ n = 4, SIV+MSC+ n = 5). (E) Spearman’s correlation between SIV-specific IFN-γ CD8+ T cell response and frequency of proliferating CD8+ T cells (SIV+ n = 3 and SIV+MSC+ n = 5). (F) Frequency of granzyme B (GZMB) expression in CD8+ T cells (SIV+MSC+ vs. SIV+ is P = 0.06, NS) (SIV– n = 11, SIV+ n = 4, and SIV+MSC+ n = 5). (G) Spearman’s correlation analysis relating the frequency of GZMB+ CD8+ T cells with plasma SIV viral loads (P = 0.08, NS) (SIV+ n = 4, SIV+MSC+ n = 5). (H and I) Heatmap displays differential expression of genes associated with T cell cytotoxicity and activation. Significant (*FDR < 0.1) and trending (*P < 0.1; Δ < 0.05) genes annotated. Data represent the mean (± SEM) for each time point. Significance was determined using the 1-way ANOVA with Holm-Sidak post hoc testing for multiple comparisons (A), the Mann- Whitney U test (B and D), Spearman’s rank correlation with linear regression (C, E, and G), or Kruskal-Wallis with Dunn’s post hoc testing (F). *P < 0.05 and **P ≤ 0.01. Gray arrow represents the first MSC administration.