Neuropilin-1 Regulates the Secondary CD8 T Cell Response to Virus Infection.

Neuropilin-1 (Nrp1) 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 that 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 reexposure to virus led to an enhanced secondary response. Interestingly, these effects were observed only in mice infected with a persistent strain of murine gammaherpesvirus and not with a nonpersistent 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 anticancer therapies focus on inhibition of Nrp1 to restrict tumor growth, and so knowledge of how Nrp1 blockade may affect the CD8 T cell response will provide a better understanding of treatment consequences.