Establishing peripheral CD8+ T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment to tumor immunity since tumors are derived from self-tissue and often induce T cell tolerance and dysfunction. Thus, understanding the mechanisms that regulate T cell tolerance versus immunity has important implications for human health. Signals received from the tissue environment largely dictate whether responding T cells become activated or tolerant. For example, induced expression and subsequent ligation of negative regulatory receptors on the surface of self-reactive CD8+ T cells are integral in the induction of tolerance. We utilized a murine model of T cell tolerance to more completely define the molecules involved in this process. We discovered that, in addition to other known regulatory receptors, tolerant self-reactive CD8+ T cells distinctly expressed the surface receptor neuropilin-1 (Nrp1). Nrp1 was highly induced in response to self-antigen, but only modestly when the same antigen was encountered under immune conditions, suggesting a possible mechanistic link to T cell tolerance. We also observed a similar Nrp1 expression profile on human tumor infiltrating CD4+ and CD8+ T cells. Despite high expression on tolerant CD8+ T cells, our studies revealed that Nrp1 had no detectable role in the tolerant phenotype. Specifically, Nrp1-deficient T cells displayed the same functional defects as wild-type self-reactive T cells, lacking in vivo cytolytic potential, IFNγ production, and antitumor responses. While reporting mostly negative data, our findings have therapeutic implications, as Nrp1 is now being targeted for human cancer therapy in clinical trials, but the precise molecular pathways and immune cells being engaged during treatment remain incompletely defined.Research reported in this publication was supported by the National Institute of Allergy and Infectious Disease/National Institutes of Health (R01AI087764) to RMT, by a Cancer Research Institute Investigator Award to RMT, and by a National Cancer Institute/National Institutes of Health fellowship (F30CA180375) to SRJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Jackson, S. R., Berrien-Elliott, M., Yuan, J., Hsueh, E. C., & Teague, R. M. (2014). Neuropilin-1 expression is induced on tolerant self- Reactive cd8+ t cells but is dispensable for the tolerant phenotype. PLoS ONE, 9(10). https://doi.org/10.1371/journal.pone.0110707