The Role of Bone Marrow T Cells in Regulating Hematopoietic Stem Cell Function.

Abstract 2349

After immune activation, effector/memory T cells, including virus-specific CD8 T cells, are known to migrate to the bone marrow (BM), where they can be maintained by the production of IL-15 by the stroma; however, it is not yet known whether these T cells also have a function at this site. Since depletion of T cells from allogenic BM grafts compromises HSC engraftment, we hypothesize that T cells can directly influence the balance between differentiation and self-renewal of hematopoietic stem cells (HSCs). To test the ability of T cells to affect hematopoiesis, we performed co-cultures of HSCs and T cells isolated from murine BM. We found that T cells localized in the BM are able to enhance HSC differentiation as well as their self-renewal capacity. This feature is specific for BM central memory (CM) CD8 T cells, since other T cell subsets are not able to affect HSCs to the same extent. Moreover, depletion of CM CD8 T cells from the total BM T cell pool abrogates the impact on HSC differentiation and self-renewal, indicating that this particular T cell population is both sufficient and required for the observed effects. BM CM CD8 T cells do not affect quiescence of HSCs, but do enhance their proliferative capacity, and we found that supernatant from CM CD8 T cells is sufficient for this effect. Interestingly, competitive transplantation assays showed that HSCs cultured with CM CD8 T cells-derived supernatant contribute much better to leukocyte formation than medium-treated HSCs. This effect is seen in both the myeloid and lymphoid compartment, indicating that CM CD8 T cells are able to release soluble factors that support and enhance the multilineage reconstitution capacity of HSCs. Functional studies with blocking antibodies or knock-out mice showed that the supernatant-mediated effect is not caused by the hematopoietic cytokines IL3, IL6, IL21, GM-CSF, RANTES, TNFα or IFNγ. Preliminary data indicate that this feedback mechanism of the immune system on the hematopoietic process in the bone marrow is also present in the human situation, since autologous BM T cells increase the numbers of human HSCs, as well as their differentiation capacity.

Overall, these findings demonstrate that T cells have an important function in the BM and that especially CD8 TCM cells can directly influence HSC homeostasis. We postulate that this feedback mechanism of the immune system on the hematopoietic process in the BM is particularly relevant during viral infection, as the efficient migration of virus-specific CD8 T cells to the BM could well benefit the replenishment of the HSC/progenitor cell compartment and restoration of blood cell numbers that got lost upon infection.