ABSTRACT
CD4+ CD25+ T regulatory (Treg) cells are critical mediators of peripheral self-tolerance and immune homeostasis. In this study, we characterized the ability of naturally occurring CD4+ CD25+ cells from the wild-type mice to modulate the immune response to administered coagulation factor VIII (FVIII) in FVIII-deficient mice. For the cell therapy, CD4+ CD25+ cells and CD4+ CD25- cells were purified from the spleens of wild-type normal mice and administered to FVIII-deficient mice prior to four injections of recombinant FVIII (rFVIII). The titre of FVIII antibodies and antibodies with inhibitory activity against FVIII was lower in the mice treated with natural CD4+ CD25+ cells or CD4+ CD25- cells compared with the mice treated only with rFVIII. We also demonstrated that CD4+ CD25- cells could differentiate to acquire the Treg phenotype expressing CD25 and FoxP3 if stimulated in vitro. These observations provide evidence that Treg cells can be used for designing cell therapy for controlling the immune response to FVIII.
Subject(s)
Factor VIII/immunology , Hemophilia A/immunology , T-Lymphocytes, Regulatory/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Factor VIII/administration & dosage , Flow Cytometry , Mice , Mice, 129 Strain , T-Lymphocytes, Regulatory/metabolismABSTRACT
In this paper, we show that the transcription factor GATA3 is dynamically expressed during hindbrain development. Function of GATA3 in ventral rhombomere (r) 4 is dependent on functional GATA2, which in turn is under the control of Hoxb1. In particular, the absence of Hoxb1 results in the loss of GATA2 expression in r4 and the absence of GATA2 results in the loss of GATA3 expression. The lack of GATA3 expression in r4 inhibits the projection of contralateral vestibuloacoustic efferent neurons and the migration of facial branchiomotor neurons similar to Hoxb1-deficient mice. Ubiquitous expression of Hoxb1 in the hindbrain induces ectopic expression of GATA2 and GATA3 in ventral r2 and r3. These findings demonstrate that GATA2 and GATA3 lie downstream of Hoxb1 and provide the first example of Hox pathway transcription factors within a defined population of vertebrate motor neurons.
