Mobilization of Tissue-Resident Memory CD4+ T Lymphocytes and Their Contribution to a Systemic Secondary Immune Reaction

While it is generally accepted that tissue-resident memory T lymphocytes protect host tissues from secondary immune challenges, it is unclear whether, and if so, how they contribute to systemic secondary immune responses. Here we show that when individuals with an established immunological memory to measles, mumps and rubella viruses are re-challenged with the measles-mumps-rubella (MMR) vaccine, tissue-resident memory CD4+ T cells are mobilized into the blood within 16 to 48 hours after vaccination before disappearing again soon after. The mobilization of tissue-resident memory T cells was found to be cognate: memory CD4+ T lymphocytes that recognize other antigens, e.g. tetanus toxin, are not mobilized, unless they cross-react with antigens present in the vaccine. Post immunization, mobilized T-cell receptor Vβ clonotypes from day 1 were represented among the newly generated circulating memory CD4+ T-cell repertoire from day 14. These data demonstrate that tissue-resident memory T cells can leave their tissue and contribute significantly to secondary systemic immune responses.