Complement component C3 mediates Th1/Th17 polarization in human T-cell activation and cutaneous GVHD.
The complement system has been shown to regulate T-cell activation and alloimmune responses in GVHD. Mice deficient in the central component of complement system C3 have significantly lower GVHD-related mortality/morbidity, and C3 modulates Th1/Th17 polarization in mouse GVHD. To investigate whether anticomplement therapy has any impact on human T-cell activation, a drug candidate Compstatin was used to inhibit C3 activation in this study. We found the frequency of IFN-γ (Th1)-, IL-4 (Th2)-, IL-17 (Th17)-, IL-2- and TNF-α-producing cells were significantly reduced among activated CD4(+) cells in the presence of Compstatin. Compstatin treatment decreased the proliferation of both CD4(+) and CD8(+) T cells upon TCR stimulation. However, Compstatin does not affect the production of IL-2 and TNF-α in activated CD8(+) T cells, and the differentiation of CD8(+) T cells into distinct memory and effector subsets remained intact. Furthermore, we examined complement deposition in skin and lip biopsy samples of patients diagnosed with cutaneous GVHD. C3 deposition was detected in the squamous epithelium and dermis, blood vessels and damaged sweat glands, and was associated with gland damage and regeneration. We conclude that C3 mediates Th1/Th17 polarization in human T-cell activation and skin GVHD in patients.
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Ma
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Li
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Carreño
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Patenia
1] Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Tsai
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Xydes-Smith
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Alousi
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Champlin
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Sale
Department of Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Afshar-Kharghan
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D003176:Complement C3 / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D012871:Skin Diseases / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D003176:Complement C3; D016207:Cytokines