Yuanyuan Tian

"Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction in the host undergoing allogeneic hematopoietic stem cell transplantation"

Dendritic cells (DCs) play nonredundant roles in the regulation of both innate and adaptive immunity. However, inflammation, resulting from such conditions as chronic infection, autoimmunity and tumor progression, may significantly affect DC generation and function. Acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) impairs the generation and function of donor DCs. GVHD is induced by alloreactive T cell responses that mediate tissue injury, primarily in the skin, liver and gut. Clinical studies suggest that severe GVHD is tied to failed reconstitution of donor plasmacytoid DCs (pDCs), which are critical for regulating both immune protection and tolerance. pDCs specialize in rapidly producing large amounts of IFN-a, protecting against pathogenic infection. In spite of their importance in mediating autoimmunity, pDCs are also known to be tolerogenic. However, the mechanisms by which GVHD causes donor pDC defects remain unknown. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type-I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-r. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD. In addition, since HSPCs’ regenerative capacity is impaired during chronic infection, autoimmunity and cance, and since pDCs play crucial roles in protection against viral infections, our studies’ impact extends beyond allo-HSCT and may have broad implications for many other diseases.