The mechanisms of T-cell regulation are difficult to elucidate because of their complexity and the numerous subcategories of cell populations. There are two fundamental approaches to address this conundrum. First, it is possible to use a purified cell population and submit these cells to various assays. The second approach is to manipulate a target molecule and determine what effect this has on T-cell homeostasis in vitro and in vivo. This molecular strategy may help characterize multiple regulatory populations that use the same pathway for controlling T-cell function. Through a concerted two-pronged effort, The authors' laboratory and others have attempted to decipher different molecular pathways for regulatory cell function. Several gene knockout mouse models display a phenotype of profound lack of homeostasis in which T cells accumulate, presumably because of a defect in regulation. Dependent on the molecule disrupted, the immune cell subset being examined may no longer be appropriately regulated. Accordingly, the phenotype of exogenously added "putative" regulatory cells can then be examined by assessing their ability to control this aberrant accumulation. By using co-transplantation techniques, much information can be postulated regarding potential regulatory cell phenotype and function. Model systems with target gene manipulations involving Fas ligand, Fas, perforin, interleukin-2, and cytotoxic T-lymphocyte-associated antigen-4 exist and in all cases appear to disrupt critical cytotoxic regulatory cell function.
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