Professional Memory CD4+ T Lymphocytes Preferentially Reside and Rest in the Bone Marrow

Abstract

CD4(+) T lymphocytes are key to immunological memory. Here we show that in the memory phase of specific immune responses, most of the memory CD4(+) T lymphocytes had relocated into the bone marrow (BM) within 3-8 weeks after their generation-a process involving integrin alpha2. Antigen-specific memory CD4(+) T lymphocytes highly expressed Ly-6C, unlike most splenic CD44(hi)CD62L(-) CD4(+) T lymphocytes. In adult mice, more than 80% of Ly-6C(hi)CD44(hi)CD62L(-) memory CD4(+) T lymphocytes were in the BM. In the BM, they associated to IL-7-expressing VCAM-1(+) stroma cells. Gene expression and proliferation were downregulated, indicating a resting state. Upon challenge with antigen, they rapidly expressed cytokines and CD154 and efficiently induced the production of high-affinity antibodies by B lymphocytes. Thus, in the memory phase of immunity, memory helper T cells are maintained in BM as resting but highly reactive cells in survival niches defined by IL-7-expressing stroma cells.

Immunological memories of the bone marrow

“…When the reaction is over, their numbers contract again, first rapidly, then slowly 57, 58, 59. The “half‐life” of blood‐borne antigen‐experienced T cells in the phase of slow contraction shows a tremendous variation, ranging from 8 to 15 years, upon smallpox vaccination of humans60 to less than 40‐60 days, in mice immunized with a peptide of lymphocytic choriomeningitis virus or ovalbumin 59. In mice, the numbers of adoptively transferred and experienced CD4 + and CD8 + T cells decline with half‐lives of 15‐70 days, in the absence of antigen 61, 62.…”

“…In several intentional murine immune responses, antigen‐experienced CD4 + T lymphocytes relocated quantitatively to the bone marrow during the contraction phase, ie, within 60 days after onset of the immune reaction. After 120 days, antigen‐experienced CD4 + T lymphocytes were no longer detectable in spleen or lymph nodes, while in bone marrow, a stable population had been established 59. In contrast, the group of Jenkins described the preferential location of memory CD4 + T cells in the spleen and lymph nodes until day 160 after infection, in an immune response to Listeria monocytogenes infection 126.…”

“…Their transcriptomes are those of resting cells 33, 59, 81, 117. CD8 + memory T cells of the bone marrow express only about 0.6 pg of RNA per cell, as compared to activated CD8 + T cells, which express more than 10 pg of RNA per cell 117.…”

“…A second signal required for efficient translocation of activated CD4 + T cells is integrin α2 (VLA‐2, CD49b) 59, 145, 146. CD4 + memory T cells stained for CD49b, and thus blocked for efficient use of VLA‐2, did not immigrate into the bone marrow in adoptive transfer experiments.…”

“…This observation also suggests that the lifestyle of resident memory T cells of the bone marrow might be not so different from the lifestyle of memory plasma cells. In murine bone marrow, memory CD4 + and CD8 + T lymphocytes are found in close association if not direct contact with stromal cells 59, 117, 137, 145. They are individually dispersed throughout the parenchyme 117.…”