Thymocyte expansion and maturation: crosstalk of CD44v6 on thymocytes and panCD44 on stroma cells.
Re-acquisition of immunocompetence after allogeneic bone marrow cell (BMC) transplantation depends on intrathymic maturation of the allogeneic T progenitor cells. We recently reported that CD44 promotes progenitor homing into the thymus and T-cell maturation and now elucidate the molecular mechanisms of CD44-supported thymocyte maturation. Lethally irradiated, tumor-bearing mice, allogeneically reconstituted with T-cell-depleted BMC and a small number of common lymphoid progenitor 2 cells (CLP2) from transgenic (TG) mice, that express ratCD44v4-v7 under the Thy1 promoter, showed accelerated immunocompetent T-cell recovery compared with mice reconstituted with non-transgenic (NTG) CLP2. In addition, graft-versus-host disease was strongly reduced after tumor vaccination. TG, but not NTG double-negative (DN) thymocytes showed high proliferative potential, accompanied by constitutive association of lck with CD44. Importantly, when thymocyte adhesion was strengthened by anti-CD44, co-cultures of DN thymocytes with thymic stroma supported DN thymocyte maturation. The close contact between DN thymocytes and thymic stroma promoted persisting activation of lck and ERK1/2, particularly in CD44v6(+) DN thymocytes. Thus, intrathymic T-cell maturation in allogeneically reconstituted, leukemia-bearing hosts can be considerably accelerated by high CD44v6 expression in early thymocytes, in which proliferation-supporting signals are initiated by a crosstalk between CD44v6 on thymocytes and panCD44 on the thymic stroma.
Department of Tumor Cell Biology, University Hospital of Surgery and German Cancer Research Center, Heidelberg, Germany.
Mohini
M
Rajasagi
Rachid
R
Marhaba
Mario
M
Vitacolonna
Margot
M
Zöller
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006086:Graft vs Host Disease / Q000276:immunology; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007108:Immune Tolerance / Q000276:immunology; D007121:Immunocompetence / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D013997:Time Factors
C112697:CD44v6 antigen; D018960:Hyaluronan Receptors