Regulatory Pro-B Cell Progenitors for Cell Therapy of Type 1 Diabetes

Cell therapy of immune diseases is mostly performed using mature regulatory cell types of diverse immune lineages. We are currently investigating whether immature hematopoietic progenitor populations might also exhibit tolerogenic properties and be proposed as well for cell therapy. We have previously described that mobilization with a cocktail of G-CSF and Flt3-L conferred tolerogenic properties to multipotent hemopoietic progenitor population (MPPs) based on their capacity to promote the expansion of CD4 super(+)CD25 super(+)Foxp3 super(+) functional Tregs (Kared et al., Immunity 25, 823, 2006; Blood, 112, 2575, 2008). Adoptive transfer of as few as 10 super(4) of such mobilized MPPs prevented type 1 diabetes (T1D) in the Non Obese Diabetic (NOD) mouse model. We now describe the emergence in bone marrow incubated with the TLR-9 agonist CpG of a novel tolerogenic progenitor population, exhibiting c-kit super(lo) Sac-1 super(lo) B220 super(+) CD19 super(+) IgM super(-) phenotype, consistent with a pro-B cell development stage, further confirmed by their differentiation into mature B lymphocytes after transfer into irradiated NOD-Rag1 super(-/-) recipients. CpG-proB cells restrained effector T cell activation and expansion. This suppressive property was based on the dramatic reduction of IL-21 production by CD4 super(+)CD25 super(-) effectors resulting from an increase of the negative regulatory factor eomesodermin and a reduction of the positive regulators ICOS and c-Maf. When adoptively transferred into NOD mice, characterized by an Idd3- related excess of IL-21 that promotes T1D, CpG-proB cells efficiently prevented disease onset. Newly characterized hematopoietic progenitor populations, and not only mature regulatory subsets, might therefore provide novel tools for cell therapy of immune disorders.