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Pathogenic Bhlhe40+ GM-CSF+ CD4+ T cells promote indirect alloantigen presentation in the GI tract during GVHD. Blood 2020 02 20;135(8):568-581

Date

12/28/2019

Pubmed ID

31880771

Pubmed Central ID

PMC7033370

DOI

10.1182/blood.2019001696

Scopus ID

2-s2.0-85081142993   2 Citations

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.

Author List

Piper C, Zhou V, Komorowski R, Szabo A, Vincent B, Serody J, Alegre ML, Edelson BT, Taneja R, Drobyski WR

Authors

William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Basic Helix-Loop-Helix Transcription Factors
CD4 Antigens
CD4-Positive T-Lymphocytes
Colon
Gastrointestinal Tract
Graft vs Host Disease
Granulocyte-Macrophage Colony-Stimulating Factor
Homeodomain Proteins
Isoantigens
Mice, Inbred C57BL
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a