T-cell activation in the curious world of the intestinal intraepithelial lymphocyte

In conventional terms, when T cells encounter appropriate stimuli, they are induced to undergo molecular and physical changes that confer upon them a state of activation. Once initiated, activation generally results in a state of full T-cell responsiveness in an all-or-none manner. Uniquely, however, the intestinal intraepithelial lymphocytes (IELs) bear features that are decidedly different from those of T cells located throughout other immunological compartments in that they exhibit some but not all properties of activated T cells, yet they can be induced to move further into activation provided appropriate costimulatory signals have been received. IEL costimulatory molecules—some of which are constitutively expressed, whereas others are upregulated following T-cell receptor (TCR)/CD3 stimulation—appear to hold the key to determining the nature and magnitude of the activational process. A system of activation such as this in the intestine would be expected to have great immunological protective value for the host because it would provide an untrammeled process of T-cell activation at a barrier site where the level of antigen exposure is consistently high. Clearly, however, mechanisms must be in place to insure that the IEL activation process is not inadvertently breached. These and other issues central to the operational workings of the intestinal immune system are elaborated in this article, and a model is presented in which IEL activation can be viewed as a layered, three-stage activational process.