Infection and immunity
-
The hallmarks of pulmonary Mycobacterium tuberculosis infection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells and M. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study of M. tuberculosis infection within nonhuman primate (NHP) granulomas. ⋯ In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs during M. tuberculosis infection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity of M. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.
-
Infection and immunity · Sep 2018
High Mobility Group Protein 1 Reverses Immune System Paralysis in Late-Phase Sepsis.
High mobility group protein 1 (HMGB1) is considered to be the primary inflammatory factor triggering immune paralysis in late-phase sepsis. In this study, however, we wanted to explore the possibility of using HMGB1 to boost local differentiation of bone marrow cells (BMCs) into regulatory dendritic cells (DCs) in vivo, thereby inducing immune reversal in late-phase sepsis and improving the prognosis. For this purpose, sepsis was induced by cecal ligation and puncture (CLP). ⋯ Adoptive transfer of septic cells pretreated with HMGB1 into CLP mice attenuated sepsis. HMGB1 enhanced the redistribution of CD11c- CD45RBhigh DCs through TLR4 signaling in parabiosis models. We conclude that HMGB1 triggers immune reversal through the mobilization, redistribution, and local immune differentiation of BMCs, thereby compensating for impaired immunity and leading to sufficient bacterial eradication.