Optimal protection against Salmonella infection requires noncirculating memory

Significance Effective vaccination against Salmonella infection requires the generation of memory T cells that can be reactivated upon exposure to bacteria in a natural setting. It is unclear whether immunity requires memory T cells that continuously patrol blood, lymphatics, and tissues, whether noncirculating T cells are important, or both. We demonstrate the generation of circulating and noncirculating memory pools after immunization. However, naive mice that previously shared a blood supply with vaccinated partners received recirculating memory T cells, but did not have T cell memory with characteristics of tissue residence, resulting in a failure to acquire robust protective immunity. Thus, noncirculating tissue-resident memory T cells are vital for effective protection against Salmonella .