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 BMin 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 amousemodel 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-infiltratingCD8+ T cells ofAAmice.Moreover, inhibitingNF- κBsignaling inAAmice 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 theBMinAAmice, and inhibiting NF-κBsignalingmay represent a novel therapeutic approach to treatingAA.