Credit: NPG

Innate lymphoid cells (ILCs) are a recently described family of immune cells that have been subdivided into three main groups on the basis of their patterns of cytokine production (see further reading). Although several studies have reported key roles for ILCs in infection and inflammation, it has been unclear how ILCs interact with cells of the adaptive immune system. Hepworth et al. now show that a subset of ILCs can express MHC class II molecules and can present antigens to CD4+ T cells. Importantly, this activity suppresses pathological CD4+ T cell responses to intestinal commensal bacteria.

The authors initially characterized immune responses in mice lacking the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt), which is crucial for the development of group 3 ILCs and T helper 17 cells. They found that the RORγt-deficient animals developed splenomegaly and, compared with control mice, had increased frequencies of proliferating CD4+ T cells as well as higher serum levels of IgG that was specific for commensal bacteria. By using a chimeric system, the authors were able to show that these immune abnormalities were caused by the absence of RORγt+ ILCs, rather than by developmental or T cell defects, and that they were dependent on the presence of commensal bacteria.

RORγt+ ILCs are likely to have a crucial role in establishing tolerance to colonizing commensal bacteria

Mice that were deficient in cytokines associated with group 3 ILC function (namely interleukin-17A (IL-17A), IL-22 and IL-23) did not show a similar phenotype to RORγt-deficient mice. Thus, the regulatory activity of RORγt+ ILCs seemed to be independent of their cytokine production. To explore this further, the authors assessed gene expression profiles in RORγt+ ILCs. They found that RORγt+ ILCs were highly enriched in transcripts that are involved in the MHC class II antigen presentation pathway. Flow cytometry analyses confirmed that group 3 ILCs from both mice and humans express MHC class II molecules.

Group 3 ILCs can be further subdivided on the basis of their expression of T-bet and the activating receptor NKp46 (also known as NCR1); MHC class II-associated genes were found to be chiefly expressed by T-bet−NKp46− group 3 ILCs. Group 2 ILCs were also shown to express MHC class II molecules, although at lower levels than group 3 ILCs, whereas group 1 ILCs lacked MHC class II expression.

Functional assays carried out in vitro showed that ILCs could process proteins that had been exogenously acquired and could subsequently present peptides on MHC class II molecules to CD4+ T cells. However, whereas antigen-pulsed dendritic cells induced the proliferation of antigen-specific CD4+ T cells, antigen-pulsed MHC class II+ ILCs could not stimulate CD4+ T cell proliferation. Indeed, when ILCs were pulsed with a commensal bacteria-derived antigen, they were shown to inhibit specific T cell responses against this antigen. Similarly to RORγt-deficient animals, mice with a RORγt+ ILC-restricted deletion of MHC class II expression showed enhanced adaptive immune responses to commensal bacteria. Furthermore, these animals developed spontaneous colonic inflammation that was dependent on CD4+ T cells and could be prevented by the continuous administration of antibiotics.

In summary, this study shows that a subset of MHC class II+ group 3 ILCs can present antigens to CD4+ T cells and can suppress adaptive immune responses against the intestinal microbiota. The authors propose that, as the first immune cells to colonize the neonatal intestine, RORγt+ ILCs are likely to have a crucial role in establishing tolerance to colonizing commensal bacteria.