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Regulatory B cells suppress GVHD and prolong survival of GVHD via membrane-bound IL-35 and secretion of exosomes with membrane-bound IL-35

ABSTRACT: Interleukin 35-producing B-cells (i35-Bregs) suppress autoimmune diseases and IL-35 is immunosuppressive member of IL-12 cytokine family. It is comprised of p35 and Ebi3 subunits which are assumed to be independently secreted proteins that associate in-vivo to form non-covalently linked heterodimeric IL-35. In view of recent reports that p35 and Ebi3 are not secreted as a heterodimer but act as independent anti-inflammatory cytokines, we investigated whether i35-Bregs can suppress GVHD by secreting p35, Ebi3 or heterodimeric IL-35. Surprisingly, i35-Bregs ameliorate and prolong survival of Graft-Versus-Host-Disease (GVHD) via membrane-bound IL-35 and secrete exosomes with membrane-bound IL-35 (i35-exosomes) that upregulate checkpoint inhibitors (PD-1/LAG-3) and induce T-cell exhaustion, thereby rendering allogeneic T-cells less active, with diminished proinflammatory effects. i35-exosomes also propagate infectious tolerance mechanism by binding bystander B-lymphocytes and converting them to IL-35 producers. Adoptive transfer of i35-Bregs or i35-exosomes suppress GVHD through these mechanisms, indicating that i35-Bregs/i35-exosomes combination-immunotherapy maybe effective therapy for GVHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263242 | GEO | 2025/02/24

REPOSITORIES: GEO

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Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.

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Regulatory B cells suppress GVHD and prolong survival of GVHD via membrane-bound IL-35 and secretion of exosomes with membrane-bound IL-35

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