Biology subjects

Flores-Valdez, M. A.

Publications and source records attributed to Flores-Valdez, M. A..

2 recordsLinked to original sources

bioRxiv2025

CD8+ T cells mediate vaccination-induced lymphatic containment of latent Mycobacterium tuberculosis infection following immunosuppression, while B cells are dispensable

It is estimated that two billion people are latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Latent Mtb infection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation. The immunological correlates of protection against TB, including against reactivation of LTBI, remain largely elusive. Here, we used a mouse model of latent lymphatic Mtb infection to dissect the immunological mechanisms underlying LTBI containment versus reactivation. We show that immunosuppression-mediated reactivation of lymphatic LTBI and the subsequent spread to non-lymphatic organs can be prevented by vaccination with multiple recombinant BCG (rBCG) strains despite the deficiency of CD4+ T cells. Using spatial transcriptomics, multi-parameter imaging, network analysis and bioinformatic integration of histopathological images, we reveal that immunosuppression is associated with a distinct repositioning of non-CD4 immune cells at the edge of TB lesions within the infection-draining cervical lymph nodes. While B cells increased in numbers, they are dispensable for the containment of LTBI. Lymphatic Mtb infection in different immune cell-deficient mouse strains, antibody-mediated cell depletion and adoptive transfer experiments into highly susceptible mice unequivocally show that vaccination-mediated prevention of LTBI reactivation is critically dependent on CD8+ T cells. These findings have profound implications for our understanding of immunity to TB and the management of LTBI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/634479v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@151fdd6org.highwire.dtl.DTLVardef@1efed47org.highwire.dtl.DTLVardef@c2e7e0org.highwire.dtl.DTLVardef@555c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Sex differences in vaccine induced immunity and protection against Mycobacterium tuberculosis

Tuberculosis (TB) is a disease that has evolved with humankind for millennia, causing approximately 1.3 million deaths worldwide per annum. Although increased male affliction for TB and other infections were long known from an epidemiological perspective, our mechanistic understanding of the underlying immunological divergences is relatively recent. As such, there is insufficient knowledge regarding the sexually dimorphic immune response to TB vaccines, where no accepted correlates of protection are yet available. In this context, our goal was to explore how individual sex influences the protective effects of TB vaccines. For this purpose, we vaccinated female and male C57BL/6 mice with Bacille Calmette-Guerin (BCG) and two recombinant derivatives, VPM1002 and BCG{Delta}BCG1419c, to analyse their protective efficacy against challenge with Mycobacterium tuberculosis HN878. We found poor efficacy of BCG in males and the ability of next generation vaccine candidates to improve protection specifically in males. To determine the underlying mechanisms for the differences in survival upon vaccination between females and males, as well as, among different vaccine candidates, we analysed the distribution and persistence of the vaccine strains, in addition to vaccine-induced immune responses at various time points in draining lymph nodes and spleen. We identified sex specific differences in CD8 T cell proliferation in response to mycobacterial antigens ex vivo, 90 days post-vaccination, that associates with vaccine mediated protection against HN878. By integrating our multi-parametric datasets into principal component analysis, followed by extraction of high-variance features, we have uncovered an additional significant association of early CD4 T cell responses with late CD8 T cell responses as well as with survival post HN878 infection. In addition, we have also identified specific clusters of responding CD8 T cells in spleen post-vaccination, that are globally deficient in males as compared to females, irrespective of the BCG strain administered.

immunology↗