The major histocompatibility complex (MHC) class I and II molecules present peptide antigen to CD8+ and CD4+ T cells, respectively. As well as classical MHC molecules, the mouse MHC encodes several non-classical MHC class I-like molecules, such as the thymus leukaemia (TL) antigen, whose functions remain incompletely understood. TL is expressed almost exclusively on intestinal epithelial cells and has been proposed to have a role in presenting antigen to intestinal epithelial lymphocytes (IELs). Reporting in Science, Hilde Cheroutre and colleagues now show that TL interacts with CD8αα homodimers on IELs, with important consequences for the mucosal environment.

Cheroutre et al. used TL tetramers to identify cells that bind to TL. Most IELs were stained by the tetramers, but not splenocytes, and only a minority of thymocytes were stained. Tetramers bound equally well to TCRαβ+ and TCRγδ+ IELs, and binding was irrespective of TCR specificity. Production of the TL tetramers in insect cells ensured that peptide–TL interactions were not possible, so peptide binding to TL molecules was not a requirement for the interaction with IELs.

As TL-tetramer binding is virtually specific for IELs, IELs express the CD8αα homodimer, and TL molecules contain a CD8α-binding motif, Cheroutre and colleagues reasoned that TL might bind CD8αα. This seemed to be the case — TL tetramers showed no staining on IELs from CD8α-deficient mice, and thymocytes from CD8β knockout mice, which express CD8αα homodimers, showed elevated TL-tetramer binding in comparison to wild-type mice. Studies using surface plasmon resonance, in which the binding of TL to CD8αα molecules immobilized on a chip was assessed, confirmed a preferential and high-affinity binding of TL to CD8αα.

So, what are the immunological consequences of TL–CD8αα interactions? This was tested by stimulating CD8α-deficient and CD8α-transfected T cells (expressing the same antigen-specific TCR) with TL+ and TL− forms of peptide-pulsed presenting cells. Increased interleukin-2 (IL-2) production by the CD8αα-expressing T cells was observed when they were stimulated with the TL-positive presenting cells. This enhanced cytokine production was confirmed using antigen-stimulated transgenic IELs, and intracellular cytokine staining revealed enhanced interferon-γ (IFN-γ) production. Polyclonally-stimulated wild-type IELs also showed increased IL-2 and IFN-γ production in the presence of TL. In contrast to the cytokine results, TL–CD8αα interactions decreased the proliferative and cytotoxic responses of IELs.

The results of this study indicate that CD8αα is not a TCR co-receptor and it affects T-cell function independently of TCR specificity. The authors speculate that TL–CD8αα interactions have a role in the maintenance of barrier function and homeostasis in the gut epithelium — inhibition of proliferation would ensure that cellular expansion would not disrupt the epithelial layer, and inhibition of cytotoxicity would ensure that the integrity of the epithelial layer is maintained. Further work will be required to elucidate the precise mechanisms by which TL–CD8αα interactions exert their regulatory effects in the intestine.