Comparative immune responses toMycobacterium tuberculosisin people with latent infection or sterilizing protection

Abstract

Tuberculosis (TB) affects 2 billion people worldwide and causes 1.5 million deaths every year. There is great need for new TB vaccines that are more efficacious than the currently licensed BCG vaccine, which provides only limited protection. Our goal was to identify potential targets for new TB vaccines by characterizing the immune responses that distinguish individuals with sterilizing protection against TB (TB-resisters), defined by presence of TB-specific immune responses and absence of latent infection, from individuals with latent TB infection (LTBI-participants). Cryopreserved peripheral blood mononuclear cells (PBMC) from 13 TB-resisters and 10 LTBI-participants were analyzed by high dimensional spectral flow cytometry after overnight M. tuberculosis (Mtb) antigenic stimulation or unstimulated control. Activation of conventional and nonconventional T cells, NK cells, and antigen presenting cells (APC) was compared between the two groups. Compared with LTBI-participants, TB-resisters had significantly higher proportions of conventional and nonconventional T cells expressing granzyme B (GranzB) and PD-1, and of polyfunctional cells in unstimulated and Mtb -stimulated conditions. Conversely LTBI-participants had higher expression of CD25, CD69, CD107a, IL10 and IFNg. An unbiased cluster analysis revealed higher frequency of recently described CD8+GMM+GranzB+ T cells in unstimulated PBMC from TB-resisters than LTBI-participants. APC activation revealed very few differences between TB-resisters and LTBI-participants. An exploratory analysis of responses in 14 BCG-recipients with minimal exposure to TB showed multiple differences with TB-resisters and LTBI-participants in PBMC activation; lower polyfunctionality of T cells and APC in Mtb -stimulated PBMC; and absence of CD8+GMM+GranzB+ T cells. We conclude that combined increased T cell expression of GranzB and checkpoint inhibitors may contribute to immune protection against TB and may be targeted by new vaccines.

Advances in understanding immune homeostasis in latent tuberculosis infection

“…Flynn's team recently demonstrated that CD8 + T‐cell depletion leads to the dissemination of Mtb in monkeys and an increase in lung inflammation, indicating the necessity of CD8 + T cells for protection during early Mtb infection (Winchell et al, 2023). Similarly, a study found that LTBI patients have more iNKT CD8 + T cells, while TB‐Resister individuals have a subgroup of CD8 + GMM + GranzB + T cells that may be associated with their strong resistance (Jalbert et al, 2023). The underestimated anti‐TB function of CD8 + T cells may be related to the infective dose employed in animal models.…”

“…Later that year, this discovery was confirmed in animal models by the research teams led by Steven Porcelli and Samuel Behar (Im et al, 2008; Sada‐Ovalle et al, 2008). A recent community survey in LTBI individuals and TB‐Resisters revealed that the frequency of iNKT cells in TB‐Resisters is higher than in LTBI individuals, suggesting that iNKT cells may contribute to clearing the infectious agent before the establishment of latency (Jalbert et al, 2023).…”

“…In a recent study, Jalbert et al compared the immune responses between TB‐resisters and LTBI populations, revealing that TB‐resisters exhibit a higher abundance of CD8 + GMM + GzB + T cells compared to LTBI. Resistance to Mtb is concomitant with an increased presence of GranzB + PD1 + multifunctional T cells (Jalbert et al, 2023). Additionally, it was observed that BCG immunization generates lower levels of CD8 + GMM + GzB + T cells compared to TB‐resisters, potentially contributing to the ineffective protection of the LTBI population by BCG.…”