title: CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia.
abstract: Aplastic anemia (AA) is a disease characterized by T-cell-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells. Physiologically, T cells migrate to the BM in response to chemokines, such as SDF-1α, the ligand for CXCR4. However, how T cells traffic to the BM in AA is poorly understood. CXCR4 is aberrantly expressed in immune-mediated diseases and its regulation by nuclear factor-κB (NF-κB) in cancer models is well documented. In this study, we show that CXCR4 is highly expressed on BM-infiltrating CD4(+) and CD8(+) T cells in a mouse model of AA. Inhibiting CXCR4 in AA mice, using CXCR4(-/-) splenocytes or AMD3100, significantly reduced BM infiltration of T cells. We also report that NF-κB occupancy at the CXCR4 promoter is enhanced in BM-infiltrating CD8(+) T cells of AA mice. Moreover, inhibiting NF-κB signaling in AA mice using Bay11 or dehydroxymethylepoxyquinomicin, or transferring p50(-/-) splenocytes, decreased CXCR4 expression on CD8(+) T cells, significantly reduced BM infiltration of T cells, and strongly attenuated disease symptoms. Remarkably, therapeutic administration of Bay11 significantly extended survival of AA mice. Overall, we demonstrate that CXCR4 mediates migration of pathogenic T cells to the BM in AA mice, and inhibiting NF-κB signaling may represent a novel therapeutic approach to treating AA.
authors: Department of Veterinary and Animal Sciences, and.
authors: Christina
authors: C
authors: Arieta Kuksin
authors: Department of Veterinary and Animal Sciences, and.
authors: Gabriela
authors: G
authors: Gonzalez-Perez
authors: Department of Veterinary and Animal Sciences, and Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA.
authors: Lisa M
authors: LM
authors: Minter
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; D016328:NF-kappa B; D019718:Receptors, CXCR4
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