{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T06:31:36Z","timestamp":1765175496905,"version":"3.46.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Bystander activation has primarily focused on conventional antigen-specific T cells (T\n                      <jats:sub>MEM<\/jats:sub>\n                      ) and other innate immune cell types. However, the role of virtual memory T cells (T\n                      <jats:sub>VM<\/jats:sub>\n                      ) 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\n                      <jats:sub>VM<\/jats:sub>\n                      cells versus T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells during the early days following\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      infection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology\/Principal Findings<\/jats:title>\n                    <jats:p>\n                      Our results demonstrate that T\n                      <jats:sub>VM<\/jats:sub>\n                      and T\n                      <jats:sub>MEM<\/jats:sub>\n                      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\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture system, T\n                      <jats:sub>VM<\/jats:sub>\n                      or T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells pre-incubated with IL-12 and IL-18 (effector cells) were cultured with\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      -infected enriched peritoneal macrophages (Tc-PM, target cells). Immunofluorescence assays revealed that both T\n                      <jats:sub>VM<\/jats:sub>\n                      and T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells exhibit a highly efficient capacity to kill the parasite and induce degranulation, in contrast to na\u00efve T cells (T\n                      <jats:sub>N<\/jats:sub>\n                      ), which showed almost no cytotoxic activity. Furthermore, intracellular flow cytometry assays confirmed that both T\n                      <jats:sub>VM<\/jats:sub>\n                      and T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells produce substantial amounts of IFN\u03b3 up to 4 days p.i. when stimulated\n                      <jats:italic>in vitro<\/jats:italic>\n                      with IL-12 and IL-18, whereas T\n                      <jats:sub>N<\/jats:sub>\n                      cells fail to produce this cytokine. Accordingly, T\n                      <jats:sub>VM<\/jats:sub>\n                      and T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells exert their cytotoxic effects via IFN\u03b3 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\n                      <jats:sub>VM<\/jats:sub>\n                      cells, IFN\u03b3 signaling occurs through STAT1 in Tc-PM. Finally, analysis of human T\n                      <jats:sub>VM<\/jats:sub>\n                      cells within PBMCs, revealed increased expression of the functional marker granzymes in Chagas disease patients compared to healthy controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/Significance<\/jats:title>\n                    <jats:p>\n                      These results challenge the view that only T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells dominate early infection control. The equivalency of T\n                      <jats:sub>VM<\/jats:sub>\n                      and T\n                      <jats:sub>MEM<\/jats:sub>\n                      cells in parasite clearance suggests T\n                      <jats:sub>VM<\/jats:sub>\n                      cells are valuable innate-like contributors, providing rapid protection. Their numerical prevalence in unprimed individuals indicates T\n                      <jats:sub>VM<\/jats:sub>\n                      cells may be an underestimated component of early immunity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1674964","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T06:29:21Z","timestamp":1765175361000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bystander CD8+ conventional memory versus virtual memory T cells in the initial days post-Trypanosoma cruzi infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Maria Estefania","family":"Viano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth 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