A T follicular helper cell origin for T regulatory type 1 cells

Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+T cells into T regulatory type 1(TR1)cells,a subset of interleukin-10-producing Treg cells that do not express FOxP3.The identities of the progenitor(s)and transcriptional regulators of this T-cell subset remain unclear.Here,we show that the peptide-major histocompatibility complex class Il(pMHCll)monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCll-coated nanoparticles(pMHCll-NPs)are invariably comprised of oligoclonal subpools of T follicular helper(TFH)and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profles.Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers,respectively.Furthermore,pMHCIl-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts,and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCl-NPs.In contrast,deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion.Bcl6 and Prdm1 are also necessary for anti-CD3 mAbinduced TR1 formation.Thus,TFH cells can differentiate into TR1 cells in vivo,and BLIMP1 is a gatekeeper of this cellular reprogramming event.

Coexpression of CD163 and CD141 identifies human circulating IL-10-producing dendritic cells (DC-10)

Tolerogenic dendritic cells(DCs)are key players in maintaining immunological homeostasis,dampening immune responses,and promoting tolerance.DC-10,a tolerogenic population of human IL-10-producing DCs characterized by the expression of HLA-G and ILT4,play a pivotal role in promoting tolerance via T regulatory type 1(Tr1)cells.Thus far,the absence of markers that uniquely identify DC-10 has limited in vivo studies.By in vitro gene expression profiling of differentiated human DCs,we identified CD141 and CD163 as surface markers for DC-10.The coexpression of CD141 and CD163 in combination with CD14 and CD16 enables the ex vivo isolation of DC-10 from the peripheral blood.CD14+CD16+CD141+CD163+cells isolated from the peripheral blood of healthy subjects(ex vivo DC-10)produced spontaneously and upon activation of IL-10 and limited levels of IL-12.Moreover,in vitro stimulation of allogeneic naive CD4+T cells with ex vivo DC-10 induced the differentiation of alloantigen-specific CD49b+LAG-3+Tr1 cells.Finally,ex vivo DC-10 and in vitro generated DC-10 exhibited a similar transcriptional profile,which are characterized by an anti-inflammatory and pro-tolerogenic signature.These results provide new insights into the phenotype and molecular signature of DC-10 and highlight the tolerogenic properties of circulating DC-10.These findings open the opportunity to track DC-10 in vivo and to define their role in physiological and pathological settings.