Neuropilin-1 identifies a subset of highly activated CD8⁺ T cells during parasitic and viral infections

by Hanna Abberger, Matthias Hose, Anne Ninnemann, Christopher Menne, Mareike Eilbrecht, Karl S. Lang, Kai Matuschewski, Robert Geffers, Josephine Herz, Jan Buer, Astrid M. Westendorf, Wiebke Hansen

Neuropilin-1 (Nrp-1) expression on CD8⁺ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8⁺ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8⁺ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1⁺CD8⁺ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1⁺CD8⁺ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8⁺ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8⁺ T cells represents a very early activation marker that exacerbates deleterious CD8⁺ T cell responses during both, parasitic PbA and acute LCMV infections.