Lung microenvironment effects on T cells following Francisella tularensis vaccination

Pulmonary infections often fail to produce long-lived immune memory and the underlying mechanism(s) remain unclear. We undertook a multiomics approach to compare adaptive immunity in two bacterial infections: Bordetella pertussis and Francisella tularensis. Both infections require CD4+ T cells, but B. pertussis results in long-lived memory responses whereas F. tularensis does not. Single cell RNA sequencing and flow cytometry revealed CD4+ T cells favored proliferation immediately after secondary B. pertussis infection but stagnated during F. tularensis challenge. Instead, rapid IFN-γ production by F. tularensis-elicited T cells induced IDO1 expression in endothelial cells, depleting pulmonary tryptophan and increasing kynurenine. This metabolic shift correlated with poor T cell proliferation and retention. Additionally, IDO1 knock-out resulted in larger T cell pools and improved survival during F. tularensis infection. Imaging confirmed the spatial association of immune cell centers and IDO1-expressing macrovascular endothelial cells underscoring the microenvironment’s impact on T cell function. Our study highlights the utility of multiomics in understanding cellular interactions within complex tissues.