High antigen levels are the cause of T cell exhaustion during chronic viral infection

TLDR

Persistent viral infections cause dysfunctional T cell responses, and although a negative correlation exists between viral load and T cell activity, it remains unclear whether high antigen levels drive exhaustion or are merely a consequence, nor how antigen presentation by bone‑marrow‑derived versus infected parenchymal cells influences this process. The study aimed to determine how antigen presentation by different cell types affects CD8⁺ T cell responses during chronic LCMV clone 13 infection in mice. To investigate this, the authors generated bone‑marrow chimeric mice in which non‑BM cells lacked MHC class I, allowing assessment of antigen presentation from distinct cellular sources. Early after infection, CD8⁺ T cells expanded and produced more cytokines in BM‑chimeric mice, yet viral clearance from MHC‑I‑deficient parenchyma was impaired, and persistent antigen presentation caused progressive exhaustion within 4–6 weeks, demonstrating that sustained antigen exposure directly drives T cell exhaustion and that CTL require direct antigen‑MHC interactions for viral clearance.

Abstract

Many persistent viral infections induce dysfunctional T cell responses. Although a negative correlation exists between viral load and T cell responses during chronic infection, it is not known whether high antigen levels are the cause or just the consequence of T cell exhaustion. Furthermore, it is unclear what role antigen presentation by bone-marrow (BM) derived versus infected parenchymal cells has on T cell exhaustion. To address these issues, we examined the influence of antigen presentation by different cell types on CD8(+) T cell responses during persistent infection of mice with lymphocytic choriomeningitis virus (LCMV) clone 13. We generated BM chimeric mice, in which non-BM derived cells were MHC class I deficient. Virus-specific CD8(+) T cells in lymphoid and nonlymphoid tissues were increased in both number and ability to produce cytokines in these mice soon after infection. However, viral clearance from infected MHC I(-/-) parenchyma was significantly impaired, despite increased populations of cytokine producing CTL. The CD8(+) T cell response was overwhelmed by sustained antigen persistence, becoming increasingly exhausted within 4-6 weeks. Thus, we find that (i) sustained antigen presentation directly drives T cell exhaustion during a chronic viral infection, (ii) CTL require direct antigen-MHC interactions to clear virus-infected cells, and (iii) persistent interactions with antigen presented on both hematopoietic and nonhematopoietic cells negatively impacts virus-specific T cell responses during chronic infection.