Abnormalities of quantities and functions of linker for activations of T cells in severe aplastic anemia

Objective: Severe aplastic anemia (SAA) is a rare immune-regulated disease characterized by severe pancytopenia and bone marrow failure, caused by destruction of hematopoietic cells by the activated T lymphocytes. Linker for activation of T cells (LAT), a transmembrane adaptor protein, plays a key role in T-cell and mast cell functions. However, it remains unclear how LAT may change in patients with SAA. This study aims at understanding the role of lymphocyte LAT in SAA. Methods: The expression of LAT, related signaling molecules, and T-cell effector molecules was determined by flow cytometry. LAT mRNA was evaluated by quantitative real-time PCR. Cytokine production by cultured T cells was determined by ELISA. Results: Patients with SAA had an increased levels of LAT and both total phosphorylated LAT and of the related molecule (ZAP-70) in circulating T cells compared with normal controls. In patients with SAA, the expression of LAT was positively associated with the expression of perforin and granzyme B in CD8(+) T cells. Inhibition of LAT expression in T cells from patients with SAA decreased the activation of the CD4(+) and CD8(+) T-cell subsets. Overexpression of LAT in T cells from normal controls increased the activation of CD4(+) and CD8(+) T-cell subsets with increased apoptosis of K562 cells in coculture. Conclusions: Our findings demonstrate that dysregulation of LAT expression and activation may contribute to over-function of T cells, imbalance of Th1/Th2 subsets and thus lead to hematopoiesis failure in SAA. Immunosuppressive therapy dramatically reduced the expression of LAT making it an attractive therapeutic target in SAA.