The origin and development of type b IELs has been controversial and is unexplored in humans. Unlike type a IELs, many type b IELs expressing an α:β T-cell receptor seem not to have undergone conventional positive and negative selection (see Chapter 8), and express apparently autoreactive T-cell receptors. The absence of the CD8α:βheterodimer, however, means that these T cells have low affinity for conventional peptide:MHC complexes, because the CD8β chain binds more strongly than the CD8α chain to classical MHC molecules. Type b α:β T-cell receptor-expressing IELs therefore cannot act as self-reactive effector cells. This low affinity for self MHC molecules is also probably the reason that these cells escape negative selection in the thymus. Rather, they appear to develop via a process of so-called agonist selection, in which late double-negative/early double-positive T cells are positively selected in the thymus by unknown ligands and are released immediately to the intestine. Here they mature and are induced to express the CD8α:α homodimer under the influence of TGF-β produced by epithelial cells. Nonclassical MHC molecules expressed on the intestinal epithelium are also important for the maturation of these type b IELs. One example of this kind of selection molecule is the thymus leukemia antigen (TL), another nonclassical MHC class I molecule (see Fig. 6.26) found in certain mouse strains which does not present peptides. TL is expressed by intestinal epithelial cells and directly binds CD8α:α with high affinity.
Type b IELs expressing a γ:δ T-cell receptor also develop via agonist selection in the thymus, as part of the programmed wave of γ:δ T-cell development (see
Fig. 8.23). The expression of this receptor is driven by specific ligands in the thymus and endows these cells with the specific ability to migrate to the intestinal epithelium, where they may be further programmed by the same agonist ligand.
The local differentiation events involved in the development of type b IELs require the presence of the cytokine IL-15, which is produced in response to the microbiota and ‘trans-presented’ to IELs in a complex with the IL-15 receptor present on epithelial cells. Type b IEL development is dependent on the aryl hydrocarbon receptor (AhR), a transcription factor activated by various environmental ligands that are derived from brassica and other dietary vegetables. Mice that lack the AhR have reduced numbers of ILC3 and type b IELs and show abnormalities in epithelial barrier repair, reinforcing the view that these unusual lymphocytes play important roles in the innate immune response to local materials in the intestine.
Summary.