The differentiation and functionality of virus-specific T cells during acute viral infections are crucial for establishing long-term protective immunity. While numerous molecular regulators impacting T cell responses have been uncovered, the role of cellular prion proteins (PrPc) remains underexplored. Here, we investigated the impact of PrPc deficiency on the differentiation and function of virus-specific T cells using the lymphocytic choriomeningitis virus (LCMV) Armstrong acute infection model. Our findings reveal that Prnp-/- mice exhibit a robust expansion of virus-specific CD8+ T cells, with similar activation profiles as wild-type mice during the early stages of infection. However, Prnp-/- mice had higher frequencies and numbers of virus-specific memory CD8+ T cells, along with altered differentiation profiles characterized by increased central and effector memory subsets. Despite similar proliferation rates early during infection, Prnp-/- memory CD8+ T cells had decreased proliferation compared with their wild-type counterparts. Additionally, Prnp-/- mice had higher numbers of cytokine-producing memory CD8+ T cells, indicating a more robust functional response. Furthermore, Prnp-/- mice had increased virus-specific CD4+ T cell responses, suggesting a broader impact of PrPc deficiency on T cell immunity. These results unveil a previously unrecognized role for PrPc in regulating the differentiation, proliferation, and functionality of virus-specific T cells, providing valuable insights into immune system regulation by prion proteins during viral infections.
Keywords: LCMV; T cells; memory T cells; prions; viral infection.
© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists.