Resident memory CD4⁺ T lymphocytes mobilize from bone marrow to contribute to a systemic secondary immune reaction

Resident memory T lymphocytes (T_RM ) of epithelial tissues and the Bm protect their host tissue. To what extent these cells are mobilized and contribute to systemic immune reactions is less clear. Here, we show that in secondary immune reactions to the measles-mumps-rubella (MMR) vaccine, CD4⁺ T_RM are mobilized into the blood within 16 to 48 h after immunization in humans. This mobilization of T_RM is cognate: T_RM recognizing other antigens are not mobilized, unless they cross-react with the vaccine. We also demonstrate through methylome analyses that T_RM are mobilized from the Bm. These mobilized cells make significant contribution to the systemic immune reaction, as evidenced by their T-cell receptor Vβ clonotypes represented among the newly generated circulating memory T-cells, 14 days after vaccination. Thus, T_RM of the Bm confer not only local, but also systemic immune memory.