Mobilization of tissue-resident memory CD4⁺T lymphocytes and their contribution to a systemic secondary immune reaction

Abstract

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 in human individuals with an established immune memory to measles, mumps and rubella viruses, when challenged with the measles-mumps-rubella (MMR) vaccine again, tissue-resident memory CD4 + T cells are mobilized into the blood within 16 to 48 hours after vaccination. These cells then leave the blood again, and apparently contribute to the systemic secondary immune reaction, as is evident from the representation of mobilized T cell receptor Vβ clonotypes among newly generated circulating memory T lymphocytes, from day 7 onwards. Mobilization of the tissue-resident memory T cells is cognate, in that memory T lymphocytes recognizing other antigens, e.g. tetanus toxin, are not mobilized, unless they cross-react with the vaccine. These data originally demonstrate the essential contribution of tissue-resident memory T cells to secondary systemic immune responses, confirming that immunological memories to systemic pathogens are maintained (also) by tissue-resident memory T cells. In practical terms, the present work defines day 1 to 2 after antigenic challenge as a time window to assess the entire immunological T cell memory for a certain pathogen, including mobilized tissue-resident memory T cells, and its correlates of effectivity. Capsule summaryThe study demonstrates the rapid and cognate mobilization of tissue-resident memory CD4 + T cells into the blood upon antigenic rechallenge, and their contribution to secondary systemic immune responses.

Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential

“…We hypothesized that antigen-specific stimulation may initiate their mobilization into the blood, allowing further expansion and redistribution into the peripheral tissues for broader spatial coverage of protective immunity, as has been suggested recently in the mouse (21). This phenomenon would be consistent with a recently published study that suggested tight kinetics for T RM cell tissue exit and reentry upon antigen-specific T cell stimulation by vaccination (23).…”

Maintenance of quiescent immune memory in the bone marrow

“…It would be intriguing to speculate that there is a functional division of labor between CD69 + and CD69 − memory T cells of the bone marrow in secondary immune reactions: CD69 + memory T cells as bona fide tissue‐(bone marrow‐) resident memory cells remaining in the bone marrow upon reactivation and providing local protection of the hematopoietically so important tissue, and CD69 − memory T cells with the ability to leave the bone marrow and participating in the systemic immune responses and germinal center reactions in secondary lymphoid organs. In recall immune responses an initial wave of antigen‐reactive memory T cells can be observed already 16–48 h after vaccination [103], suggesting direct mobilization into the blood from their tissue of residence (Fig. 2).…”