Pathogenic Bhlhe40+ GM-CSF+ CD4+ T cells promote indirect alloantigen presentation in the GI tract during GVHD

Abstract

Gastrointestinal (GI) tract involvement is the major cause of morbidity and mortality in acute graft-versus-host disease (GVHD), and pathological damage is largely attributable to inflammatory cytokine production. Recently, granulocyte-macrophage colony stimulating factor (GM-CSF) has been identified as a cytokine that mediates inflammation in the GI tract, but the transcriptional program that governs GM-CSF production and the mechanism by which GM-CSF links adaptive to innate immunity within this tissue site have not been defined. In the current study, we identified Bhlhe40 as a key transcriptional regulator that governs GM-CSF production by CD4+ T cells and mediates pathological damage in the GI tract during GVHD. In addition, we observed that GM-CSF was not regulated by either interleukin 6 (IL-6) or IL-23, which are both potent inducers of GVHD-induced colonic pathology, indicating that GM-CSF constitutes a nonredundant inflammatory pathway in the GI tract. Mechanistically, GM-CSF had no adverse effect on regulatory T-cell reconstitution, but linked adaptive to innate immunity by enhancing the activation of donor-derived dendritic cells in the colon and subsequent accumulation of these cells in the mLNs. In addition, GM-CSF promoted indirect alloantigen presentation, resulting in the accumulation of donor-derived T cells with a proinflammatory cytokine phenotype in the colon. Thus, Bhlhe40+ GM-CSF+ CD4+ T cells constitute a colitogenic T-cell population that promotes indirect alloantigen presentation and pathological damage within the GI tract, positioning GM-CSF as a key regulator of GVHD in the colon and a potential therapeutic target for amelioration of this disease.

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

“…2A). Whereas gastrointestinal GVHD is extremely common in clinical cases, it is also an organ that is predominantly damaged by conditioning regimens (27,28). Thus, the absence of a conditioning regimen in our model may prevent the induction of gastrointestinal GVHD, although additional experiments are required to confirm this.…”

Retinoic Acid Signaling Modulates Recipient Gut Barrier Integrity and Microbiota After Allogeneic Hematopoietic Stem Cell Transplantation in Mice

“…Donor T cells are the major pathogenic cells causing GVHD ( 51 ). We found no significant differences in donor T cell expansion and Treg reconstitution after BMT between VAN and VAH mice.…”

BHLHE40 Regulates IL-10 and IFN-γ Production in T Cells but Does Not Interfere With Human Type 1 Regulatory T Cell Differentiation

“…The involvement of BHLHE40 in different T cell subsets opens up questions surrounding BHLHE40 modulation of Tr1 cells in vivo. Currently, studies on the in vivo functions of BHLHE40 have largely focused on the pro-inflammatory contributions of non-Tr1 T cells in the gastrointestinal tract ( 28 , 29 ) and the nervous system ( 39 ). Therefore, tracking the explicit expression patterns of BHLHE40 in Tr1 cells at steady-state and during disease to see if BHLHE40 modulation contributes to disease manifestation would be invaluable.…”

“…BHLHE40 additionally has a broader regulatory role over cytokine expression in other T cell subsets and disease contexts. In response to Heligmosomoides polygyrus , it ensures expression of Th2 cytokines such as IL-4 and IL-5 ( 22 ) and during graft-versus-host disease, it mediates gastrointestinal inflammation via GM-CSF production ( 29 ). The multifunctional role of BHLHE40 in different CD4 + T cell subsets, including Tr1 cells, has yet to be delineated in human cells.…”