Gaining insights into the ontogeny and activation of T cells through the use of gene-targeted mutant mice

Abstract

T lymphocytes recognize peptides bound to major histocompatibility complex products through the alpha- and beta-chains of their T-cell antigen receptors (TcR). The interaction between T cells and target cells or antigen-presenting cells is also assisted by a series of other accessory cell surface proteins. Probably most characterized of these accessory molecules are CD4 and CD8, which are differentially expressed on helper and cytotoxic T-cell lineages, respectively. Upon engagement of ligands by these cell surface proteins, a series of signals are transduced intracytoplasmically via associated protein kinases, such as the lymphocyte-specific tyrosine kinase lck. Another component important to signaling is the cell surface tyrosine phosphatase CD45, which through alternative splicing occurs in different isoforms on various hematopoietic and lymphopoietic cells. Despite the complexity of the TcR, signals generated via these receptors are thought to be insufficient to fully activate T lymphocytes. Many investigators believe that collateral (costimulatory) signaling of the CD28 molecule and the TcR facilitates complete activation of T lymphocytes. In addition, immune responses are regulated by a number of cytokines and soluble factors. Finally, at a very basic level, transcriptional factors, such as those involved in controlling interferon production, are important in T-cell development and immune responses. In an attempt to better understand the roles of these molecules in T lymphocyte function and ontogeny, we generated a series of mutant mice with disruptions in the genes coding for these molecules. The following discussion reports on some of the findings observed with these mutant animals.