Neuropilin-1 regulates the secondary CD8 T cell response to virus infection

Abstract

Neuropilin-1 plays important roles in axonal guidance in neurons, and in the growth of new blood vessels. There is also a growing appreciation for roles played by neuropilin-1 in the immune response. This molecule is important for the function of regulatory T cells, however roles in other T cell populations have not been identified. Here we show that neuropilin-1 is expressed during the peak of the antiviral CD8 T cell response during murine gammaherpesvirus infection. Using a conditional knockout model, we deleted Nrp1 either before infection, or after CD8 T cell memory had been established. We found deletion of Nrp1 skewed the acute CD8 T cell response toward a memory precursor-like phenotype, however the ensuing resting memory response was similar regardless of Nrp1 expression. Interestingly Nrp1 deletion had differing effects on the recall response depending on the timing of deletion. When deleted before infection, Nrp1 deficiency inhibited the secondary response. Deletion just prior to re-exposure to virus lead to an enhanced secondary response. Interestingly these effects were observed only in mice infected with a persistent strain of murine gammaherpesvirus, and not a non-persistent mutant strain. These data highlight a multifaceted role for neuropilin-1 in memory CD8 T cell differentiation, dependent upon the stage of the T cell response and characteristics of the infectious agent. Several therapeutic anti-cancer therapies focus on inhibition of Nrp1 to restrict tumor growth, so knowledge of how Nrp1 blockade may affect the CD8 T cell response will provide a better understanding of treatment consequences. Importance CD8 T cell responses are critical to control both virus infections and tumors. The ability of these cells to persist for long periods of time can result in lifelong immunity, as relatively small populations of cell can expand rapidly to counter re-exposure to the same insult. Understanding the molecules necessary for this rapid secondary expansion is critical if we are to develop therapies that can provide lifelong protection. This report shows an important and complex role for the molecule neuropilin-1 in the secondary response. Several cancer therapies targeting neuropilin-1 are in development, and this work will lead to better understanding of the effect these therapies could have upon the protective CD8 T cell response.