The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure

Abstract

The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet-/-). In comparison with normal C57BL6 (B6) control mice, T-bet-/- mice had normal cellular composition in lymphohematopoietic tissues, but T-bet-/- lymphocytes were functionally defective. Infusion of 5 × 106 T-bet-/- lymph node (LN) cells into sublethally irradiated, major histocompatibility complex-mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet-/- LN-cell dose to 10 to 23 × 106 per recipient led to only mild hematopoietic deficiency. Recipients of T-bet-/- LN cells had no expansion in T cells or interferon-γ- producing T cells but showed a significant increase in Lin-Sca1 +CD117+CD34- BM cells. Plasma transforming growth factor-β and interleukin-17 concentrations were increased in T-bet-/- LN-cell recipients, possibly a compensatory upregulation of the Th17 immune response. Continuous infusion of interferon-γ resulted in hematopoietic suppression but did not cause T-bet-/- LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.