AUTHOR=Sarkander Jana , Hojyo Shintaro , Mursell Mathias , Yamasaki Yuzuru , Wu Tsung-Yen , Tumes Damon J. , Miyauchi Kosuke , Tran Cam Loan , Zhu Jinfang , Löhning Max , Hutloff Andreas , Mashreghi Mir-Farzin , Kubo Masato , Radbruch Andreas , Tokoyoda Koji TITLE=Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03113 DOI=10.3389/fimmu.2019.03113 ISSN=1664-3224 ABSTRACT=

CD4 T cell memory is fundamental for long-lasting immunity and effective secondary responses following infection or vaccination. We have previously found that memory CD4 T cells specific for systemic antigens preferentially reside in the bone marrow (BM) and arise from splenic CD49b+T-bet+ CD4 T cells. However, how BM-homing memory precursors are generated during an immune reaction is unknown. We show here that BM memory precursors are generated via augmented rates of cell division throughout a primary immune response. Treatment with the cytostatic drug cyclophosphamide or blockade of the CD28/B7 co-stimulatory pathway at the beginning of the contraction phase abrogates the generation of BM memory precursors. We determine that, following a critical number of cell divisions, memory precursors downregulate CCR7 and upregulate IL-2Rβ, indicating that loss of CCR7 and gain of IL-2 signal are required for the migration of memory precursors toward the BM.