Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa.
Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet(+) T-cell effectors was associated with both increased proliferation and the expression of the type I chemokine receptor CXCR3. Concurrently, in both infiltrating cells and keratinocytes, we observed increased expression of the CXCR3 ligand MIG (CXCL9) and interleukin-15 (IL-15), type I interferon (IFN)-inducible factors that support the migration, type I differentiation, and expansion of alloreactive effectors. In severely affected mucosa, we observed high levels of MxA, a protein specifically induced by type I IFN, and signal transducer and activator of transcription 1 (STAT1) phosphorylation, a critical step in the IFN-signaling pathway, along with increased numbers of plasmacytoid dendritic cells. These data challenge the current paradigm of cGVHD as a type II cytokine-driven disorder and support the model that oral cGVHD results from type I IFN-driven immigration, proliferation, and differentiation of T-bet(+) type I T effectors. The clinical trials are registered at http://www.clinicaltrials.gov as NCT00331968.
Imanguli
Matin M
MM
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Swaim
William D
WD
League
Stacy C
SC
Gress
Ronald E
RE
Pavletic
Steven Z
SZ
Hakim
Frances T
FT
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D054370:Chemokine CXCL9 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007156:Immunologic Memory; D007370:Interferon Type I / Q000276:immunology*; D019409:Interleukin-15 / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology; D017512:Lichenoid Eruptions / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000276:immunology / Q000473:pathology; D054367:Receptors, CXCR3 / Q000378:metabolism; D012720:Severity of Illness Index; D013280:Stomatitis / Q000276:immunology* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult; D000098815:T-bet Transcription Factor
C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054370:Chemokine CXCL9; D007370:Interferon Type I; D019409:Interleukin-15; D054367:Receptors, CXCR3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor