Bystander CD8+ conventional memory versus virtual memory T cells in the initial days post-Trypanosoma cruzi infection

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Background Bystander activation has primarily focused on conventional antigen-specific T cells (T MEM ) and other innate immune cell types. However, the role of virtual memory T cells (T VM ) has been largely overlooked, despite their numerical superiority and highly cytotoxic phenotype. Bystander activation is particularly relevant in infections caused by intracellular pathogens. In this study, we aimed to compare the bystander activation potential of T VM cells versus T MEM cells during the early days following T. cruzi infection. Methodology/Principal Findings Our results demonstrate that T VM and T MEM cells, evaluated by flow cytometry, are present but do not undergo significant changes in frequency during the first four days post-infection (p.i.). In an in vitro co-culture system, T VM or T MEM cells pre-incubated with IL-12 and IL-18 (effector cells) were cultured with T. cruzi -infected enriched peritoneal macrophages (Tc-PM, target cells). Immunofluorescence assays revealed that both T VM and T MEM cells exhibit a highly efficient capacity to kill the parasite and induce degranulation, in contrast to naïve T cells (T N ), which showed almost no cytotoxic activity. Furthermore, intracellular flow cytometry assays confirmed that both T VM and T MEM cells produce substantial amounts of IFNγ up to 4 days p.i. when stimulated in vitro with IL-12 and IL-18, whereas T N cells fail to produce this cytokine. Accordingly, T VM and T MEM cells exert their cytotoxic effects via IFNγ production, rather than NKG2D, which subsequently activates reactive oxygen species (ROS) and Nitric Oxide (NO) pathways in Tc-PM. Additionally, we demonstrate that in T VM cells, IFNγ signaling occurs through STAT1 in Tc-PM. Finally, analysis of human T VM cells within PBMCs, revealed increased expression of the functional marker granzymes in Chagas disease patients compared to healthy controls. Conclusions/Significance These results challenge the view that only T MEM cells dominate early infection control. The equivalency of T VM and T MEM cells in parasite clearance suggests T VM cells are valuable innate-like contributors, providing rapid protection. Their numerical prevalence in unprimed individuals indicates T VM cells may be an underestimated component of early immunity.

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