Biology subjects

Cavallo, K.

Publications and source records attributed to Cavallo, K..

5 recordsLinked to original sources

bioRxiv2025

BCG vaccination elicits protection against Mtb infection mediated by two phases of T cell immunity

Abstract/SummaryVaccine development for tuberculosis is a global priority. Our studies using Collaborative Cross (CC) mice show that genetic diversity influences the efficacy of BCG, the most widely used TB vaccine. BCG vaccination of CC042 mice reduces their lung bacillary burden and increases their survival following low-dose aerosol Mycobacterium tuberculosis infection (MTBI), despite impaired T cell trafficking from a defective Itgal gene. Early protection requires the presence of T cells at the time of BCG vaccination but is not mediated by B cell or T cell recall responses following MTBI. In contrast, T cell depletion following BCG vaccination reduces survival after MTBI. Thus, CC042 mice reveal two phases of immunity induced by BCG that require T cells: an early phase mediated by innate responses and a later phase mediated by effector CD4 and/or CD8 T cells. Although measurement of vaccine-induced protection 30 days after MTBI is a standard measure of vaccine efficacy in the murine TB model, we find this time point is independent of memory T cells. Our results suggest that vaccine-elicited innate responses have a larger role in protection than previously considered. The concordance between lung CFU, pathology, and survival make CC042 mice a useful model for vaccine evaluation.

immunology↗

bioRxiv2025

CD226 identifies effector CD8+ T cells during tuberculosis and costimulates recognition of Mycobacterium tuberculosis-infected macrophages

CD8+ T cells defend against Mycobacterium tuberculosis (Mtb) infection but variably recognize Mtb-infected macrophages. To define how the diversity of lung parenchymal CD8+ T cells changes during chronic infection, cells from C57BL/6J mice infected for 6- and 41-weeks were analyzed by scRNA-seq. We identified an effector lineage, including a cluster that expresses high levels of cytotoxic effectors and cytokines, and dysfunctional lineage that transcriptionally resembles exhausted T cells. The most significant differentially expressed gene between two distinct CD8+ T cell lineages is CD226. Mtb-infected IFN{gamma}-eYFP reporter mice revealed IFN{gamma} production is enriched in CD226+CD8+ T cells, confirming these as functional T cells in vivo. Purified CD226+ but not CD226- CD8+ T cells recognize Mtb-infected macrophages, and CD226 blockade inhibits IFN{gamma} and granzyme B production. Thus, CD226 costimulation is required for efficient CD8+ T cell recognition of Mtb-infected macrophages, and its expression identifies CD8+ T cells that recognize Mtb-infected macrophages. One Sentence SummaryShinkawa et al. discover that CD226 is a functional marker that distinguishes effector from dysfunctional CD8+ T cells in the Mycobacterium tuberculosis (Mtb)-infected lung and has a crucial role in costimulating CD8+ T cell recognition of Mtb-infected macrophages.

immunology↗

bioRxiv2025

CD4 T cell dysfunction is associated with bacterial recrudescence during chronic tuberculosis.

While most people contain Mycobacterium tuberculosis infection, some individuals develop active disease, usually within two years of infection. Why immunity fails after initially controlling infection is unknown. C57BL/6 mice control Mycobacterium tuberculosis for up to a year but ultimately succumb to disease. We hypothesize that the development of CD4 T cell dysfunction permits bacterial recrudescence. We developed a reductionist model to assess antigen-specific T cells during chronic infection and found evidence of CD4 T cell senescence and exhaustion. In C57BL/6 mice, CD4 T cells upregulate coinhibitory receptors and lose effector cytokine production. Single cell RNAseq shows that only a small number of CD4 T cells in the lungs of chronically infected mice are polyfunctional. While the origin and causal relationship between T- cell dysfunction and recrudescence remains uncertain, we propose T cell dysfunction leads to a feed-forward loop that causes increased bacillary numbers, greater T cell dysfunction, and progressive disease.

immunology↗

bioRxiv2022

Host genetic background is a barrier to vaccine-induced protection against infection

The heterogeneity of immune responses observed in humans is difficult to model in standard inbred laboratory mice. To capture the diversity inherent in mice and better understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis, 24 unique Collaborative Cross (CC) recombinant inbred mouse strains and the C57BL/6 reference strain were vaccinated with or without BCG, and then challenged with low-dose aerosolized virulent M. tuberculosis. In contrast to standard lab strains, BCG protected only half of the CC strains tested. Furthermore, BCG efficacy is dissociable from inherent susceptibility to TB. As these strains differed primarily in the genes and alleles they inherited from the CC founder strains, we conclude that the host genetic background has a major influence on whether BCG confers protection against M. tuberculosis infection and indicates that host genetics should be considered as an important barrier to vaccine-mediated protection. Importantly, we wished to identify the components of the immune response stimulated by BCG, which were subsequently recalled after Mtb infection and associated with protection. The T cell immune response following BCG vaccination and Mtb challenge was extensively characterized. Although considerable diversity was observed, BCG vaccination had little impact on the composition of T cells recruited and maintained in the lung after infection. Instead, the variability was largely shaped by the genetic background. We developed models to detect vaccine-induced differences, which identified immune signatures associated with BCG-elicited protection against TB. Importantly, even when categorized as susceptible vs. resistant, and protected vs. unprotected, many of the protected CC strains had unique flavors of immunity, indicating multiple paths to protection. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

immunology↗

bioRxiv2021

CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

CD4 T cells are essential for immunity to tuberculosis because they produce cytokines including interferon-{gamma}. Whether CD4 T cells act as "helper" cells to promote optimal CD8 T cell responses during Mycobacterium tuberculosis is unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growth in vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 T cell responses against M. tuberculosis infection in vitro and in vivo. We infer vaccines that elicit both CD4 and CD8 T cells are more likely to be successful than vaccines that elicit only CD4 or CD8 T cells.

immunology↗