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Metalloproteinase‐Dependent Control of Thymocyte Differentiation and Proliferation
Author(s) -
Haidl I. D.,
Falk I.,
Nerz G.,
Eichmann K.
Publication year - 2006
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2006.01820.x
Subject(s) - thymocyte , stromal cell , biology , microbiology and biotechnology , double negative , cd8 , t cell receptor , t cell , cellular differentiation , downregulation and upregulation , matrix metalloproteinase , immunology , cancer research , immune system , biochemistry , gene
The development of T cells in the thymus is dependent on interactions between thymocytes and thymic stromal cells, on stimulation by growth factors, and on the binding to and migration along extracellular matrix (ECM) components. As metalloproteinases (MP) are involved in processes such as growth factor release and ECM modelling, we assessed the effect of MP inhibitors on T‐cell development using fetal thymic organ culture systems. MP inhibitors significantly reduced the numbers of CD4/CD8 double‐positive (DP) and mature single‐positive thymocytes generated, correlated with a reduced number of cell cycles between the double‐negative (DN)3 and DP stages. The progression of early thymocyte progenitors through the DN1–4 stages of development was also severely affected, including incomplete upregulation of CD25, decreased DN3 cell numbers, reduced rearrangement of the T‐cell receptor (TCR)‐ β locus and expression of intracellular TCR‐ β by fewer DN3 cells. When purified DN1 cells were utilized as donor cells in reaggregate thymic organ cultures, essentially no DP thymocytes were produced in the presence of MP inhibitors. The results suggest that MP inhibitors affect the differentiation of developing thymocytes before, and reduce proliferation after, pre‐TCR‐mediated selection.