Type a IELs (top panels) are conventional CD8 cytotoxic T cells that recognize peptides derived from viruses or other intracellular pathogens bound to classical MHC class I molecules on infected epithelial cells. Type a IELs express an α:β T‑cell receptor and the CD8α:β heterodimer co‑receptor. Type b IELs carrying the CD8α:α homodimer (bottom panels) recognize MIC‑A and MIC‑B using the receptor NKG2D and are activated by IL‑15. Human epithelial cells that have been stressed by infection or altered cell growth or by a toxic peptide from the protein α‑gliadin (a component of gluten) upregulate expression of the nonclassical MHC class I molecules MIC‑A and MIC‑B and produce IL‑15. Both types of IELs can kill by the release of perforin and granzyme. Apoptosis of epithelial cells can also be induced by the binding of Fas ligand on the T cell to Fas on the epithelial cell.
Type b (natural) CD8 IELs can express either an α:β or a γ:δ T-cell receptor, but are distinguished by their expression of the CD8α:α homodimer. The γ:δ T cells in the intestine are enriched for particular Vγ and Vδ genes and are distinct from those found in other tissues (see Fig. 8.23). Some of the α:β receptors expressed by IELs bind nonconventional ligands, including those presented by MHC class Ib molecules (see Section 6-17). Type b IELs also express molecules typical of natural killer cells, such as the activating C-type lectin NKG2D, which binds to the two MHC-like molecules MIC-A and MIC-B. These are induced on intestinal epithelial cells in response to cellular injury, stress, or ligation of TLRs (see Section 6-16). The injured cells can then be recognized and killed by the IELs, a process that is enhanced by the production of IL-15 by the damaged epithelial cells. Like innate immune cells, type b IELs constitutively express genes associated with inflammation, such as the production of high levels of cytotoxic molecules, NO, and pro-inflammatory cytokines and chemokines. Their role in the gut may be the rapid recognition and elimination of epithelial cells that express an abnormal phenotype as a result of stress or infection (see Fig. 12.14, bottom panels). Type b IELs are also thought to be important in aiding the repair of the mucosa after inflammatory damage: they stimulate the release of antimicrobial peptides, thus helping to remove the source of the inflammation; and they release cytokines such as keratinocyte growth factor, which promotes epithelial barrier function, and TGF-β, which assists tissue repair, as well as inhibiting local inflammatory reactions.
Type b IELs are kept in check by their co-expression of signaling inhibitors, including the immunomodulatory cytokine TGF-β and inhibitory receptors like those found on NK cells. The importance of these control processes is shown by the fact that inappropriate or excess activation of type b IELs may give rise to disease. For example, increased numbers of IELs expressing a γ:δ T-cell receptor are found in celiac disease, which is caused by an abnormal immune response to the wheat protein gluten (see Section 14-17). MIC-Adependent cytotoxic activity of intraepithelial T cells contributes to the intestinal damage in this condition, as certain components of gluten can stimulate the production of IL-15 by epithelial cells and increase expression of MIC-A. These processes lead to killing of epithelial cells by the activated IELs, as described above (see Fig. 12.14, bottom panels).