Expression of heat shock protein 70 blocks thymic differentiation of T cells in transgenic mice.

Heat shock protein 70 (HSP70) is involved not only in protein folding, but also in processes of differentiation and cell-cycle progression. Recently, HSP70 has been implicated in mediation of functions of some immunosuppressive agents. To study the role of HSP70 in differentiation of haematopoietic cells, we generated transgenic mice using the human inducible hsp70 gene fused to the mouse H-2K promoter. These mice develop a T-cell deficiency that is characterized by thymic hypoplasia and a significant reduction in peripheral T cells. The total number of thymocytes is about 100-fold less than that in normal mice. The majority of the thymocytes are immature T cells that express neither CD4 nor CD8 molecules, indicating that T cells are affected at an early stage of thymic differentiation. Expression of the transgenic HSP70 was detected both in bone marrow cells and in thymocytes. Furthermore, injection of normal bone marrow cells into the T-cell deficient mice led to the generation of mature T cells indicating that the T-cell deficiency was caused by the action of HSP70 in T cells. The blockage of differentiation occurred only in T cells, both alphabeta- and gammadelta-T-cell receptor (TCR)-bearing cells, but not in B cells, granulocytes, and monocytes. The observations suggest that HSP70 may inhibit a cellular process that is essential for the differentiation of early stage T cells. Further experiments using this model system will widen our understanding of HSP70 and its function on a molecular level.