Comment

Intraepithelial lymphocytes (IELs) are predominantly T cells and are found in the guts of vertebrates ranging from chickens through rodents to humans. To varying degrees in different species, IELs are also found in other epithelia. Murine epidermal IELs expand in areas of active hair growth, and intestinal IELs expand in response to coccidial infection of the gut. The numbers of human intestinal IELs, ordinarily a few per villus, are dramatically expanded in coeliac disease. However, neither the stimulus for, nor the consequences of IEL expansion are understood. Compounding this, IELs are invariably enriched relative to the systemic circulation in T cells expressing the γδ T cell receptor (TCR). Unexpectedly discovered in the 1980s, γδ cells are themselves an enigma.1

A decade ago, an hypothesis for IEL function was proposed2based on the following reasoning. In the conventional immune system, intense antigen sampling in the lymph nodes allows clonal selection of relevant B cells and T cells from a massive antigen receptor repertoire generated by somatic gene rearrangement.3 By contrast, IELs are within epithelia, and although unlikely to be sessile, they probably encounter tens rather than tens of thousands of antigens each day. Hence for IELs to be activated, their antigen receptor diversity should be correspondingly limited. Thus, their antigens are likely to be common microbial antigens, or self antigens that are general harbingers of epithelial cell “stress”, caused by infections or cell transformation. The products of non-polymorphic major histocompatibility complex (MHC) genes, of hitherto unknown function, were proposed to be such harbingers.2

By now it has become clear that IEL antigen receptor diversity is indeed limited. In the extreme, almost all γδ+ IELs of murine skin, known as DETC (dendritic epidermal T cells), express an identical antigen …