Pathogenic Bhlhe40+ GM-CSF+ CD4+ T cells promote indirect alloantigen presentation in the GI tract during GVHD
Year: 2019
Type: article
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.
Source: Blood
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Medical College of Wisconsin, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Blockade of IL-23 for the Prevention of Graft Versus Host Disease, Regulatory T Cell Populations in Graft versus Host Disease, Impact of Microbiota on Alloimmune Responses in Transplantation, Regulation of Immune Responses to Mycobacterium tuberculosis Infection, G3008918083, UNC Oncology K12, G435608594, G4720334866, G7090640000, Medical Scientist Training Program, The microbiota and allograft rejection: novel investigations into the consequences of obesity, UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY, Mechanistic Evaluations of ILC2 Cells for the Treatment/Prevention of GVHD, The Role of Donor T Cell-Derived GM-CSF in the Pathogenesis of Gastrointestinal Acute GVHD, G9000080299, G9000082395, Center for Interdisciplinary Study of Inflammatory Intestinal DIsorders (C-IID), Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease
OpenAlex ID: W2996785110