Pathogenic Bhlhe40+ GM-CSF+ CD4+ T cells promote indirect alloantigen presentation in the GI tract during GVHD. Blood 2020 Feb 20;135(8):568-581
Date
12/28/2019Pubmed ID
31880771Pubmed Central ID
PMC7033370DOI
10.1182/blood.2019001696Scopus ID
2-s2.0-85081142993 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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 WRAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinAniko Szabo PhD Professor in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBasic 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