The Human Bone Marrow May Offer an IL-15-Dependent Survival Niche for EOMES⁺ Tr1-Like Cells

Maintenance of memory T-cells in the bone marrow and systemically depends on the homeostatic cytokines IL-7 and IL-15. An immunological memory may also exist for regulatory T-cells. EOMES⁺type-1 regulatory (Tr1)-like cells have a rapid in vivo turnover, but whether they are short-lived effector cells or are maintained long-term has not been investigated. EOMES⁺Tr1-like cells expressing GzmK were enriched among CD69⁺Ki67^-T-cells in the bone marrow of healthy donors, suggesting that they became quiescent and bone marrow-resident. Conversely, CD4⁺GzmB⁺ effector T-cells were excluded from the bone marrow-resident fraction. The dichotomy between GzmK⁺ and GzmB⁺T-cells was observed both in healthy individuals and in multiple sclerosis patients, and also among CD8⁺T-cells. Intriguingly, bone marrow-resident CD4⁺ memory T-cells expressed increased levels of IL-7Rα, while EOMES⁺Tr1-like cells were consistently IL-7Rα^lo. However, EOMES⁺Tr1-like cells expressed the IL-2/15Rβ chain, and the latter was induced upon forced expression of EOMES in primary human CD4⁺ T-cells. Finally, IL-15 rescued EOMES⁺Tr1-enriched populations from death by neglect but was not required for CD4⁺ memory T-cell survival. These findings suggest that the bone marrow may provide a survival niche for EOMES⁺Tr1-like cells. The different IL-7 and IL-15 receptor expression patterns of CD4⁺ memory T-cells and EOMES⁺Tr1-like cells suggest furthermore that they compete for different homeostatic niches.