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
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Abstract
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
1½days 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.