Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice

- Normal marrow HSPC produce IL-17/21 & other cytokines on apoptosis related TLR agonist stimulation.
- Apoptotic product/TLR stimulated normal HSPC augment IL-17+ memory CD4 & CD8 T cells in bone marrow.
- Lupus bone marrow HSPC are endogenously pre-stimulated to produce IL-17/IL-21 and other cytokines.
- In contrast to bone marrow HSPC, megakaryocyte progenitor cells (MKP) do not produce IL-17/IL-21.
- Unlike HSPC, MKP can process & present apoptotic antigens, augmenting autoimmune Th17 in lupus.

We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC). Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 1½ days of stimulation, and the best stimulators were TLR 7/8 agonist; HMGB1-DNA; TLR 9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL-17+ memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL-17+ T cells with “naïve” phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance.