Antigen presentation by type 3 innate lymphoid cells instructs the differentiation of gut microbiota-specific regulatory T cells

Kedmi, R. et al. (BioRxiv) doi: 10.1101/2021.11.19.469318

Keywords

  • Type 3 innate lymphoid cells (ILCs)

  • Antigen presentation

  • Regulatory T cells (Tregs)

 

Main Findings

The intestine sustains a state of equilibrium by simultaneously maintaining tolerance to trillions of microorganisms while defending against pathogenic organisms. Dysregulation of this can lead to intestinal inflammation. One way in which this balance is achieved is by mucosal innate and adaptive immune cells, such as regulatory T (Treg) cells. It is generally accepted that conventional (or classical) dendritic cells that migrate from tissue to lymph nodes present microbial antigens and promote the differentiation of antigen-specific T cells. The cellular basis by which gut bacteria direct mucosal T cells to specific phenotypes is poorly understood and a recent preprint by Kedmi et al. (not peer-reviewed) seeks to address this question.

 

Helicobacter hepaticus (Hh) is a pathobiont known to induce Treg cells in mesenteric lymph nodes (MLNs) following oral gavage in mice under homeostatic conditions. It should be noted that Hh can induce various T cell subsets depending on the conditions that are present. The authors found that depletion of MHC class II expression from CD11c-expressing cells in Hh-infected mice reduced the number of Hh-specific Treg cells in the MLNs. Strikingly, depletion of conventional dendritic cells failed to phenocopy this effect, which suggests that an alternative CD11c-expressing cell type is involved in the induction of Treg cells by Hh in this model. 

 

To identify the antigen presenting cell of relevance the authors used an unbiased approach with CD11c-Cre fate-mapping mice and CITE-seq technologies to show that the CD11c-expressing cell type co-expressed RORγt. These cells were identified in further experiments as group 3 innate lymphoid cells (ILC3s). In keeping with this, depletion of MHC class II expression in RORγt-expressing cells also reduced the number of Hh-specific Treg cells in the colon and the mLNs. In addition, ablation of CCR7 globally or in CD11c-expressing cells reduced the numbers of Hh-specific Treg cells, but in contrast the pathogenic TH17 cell response to Hh remained relatively unaltered. This suggests that the putative ILC3 that is presenting antigen requires trafficking to the lymph node to induce Treg cells, but that this trafficking is not required for TH17 cell differentiation.

 

Differentiation of Treg cells require TGFβ signalling which is dependent on αV integrin (ITGAV) interaction. The numbers of Hh-specific Treg cells reduced when ITGAV was depleted in CD11c-expressing cells, and ITGAV expression was found to be highest in the ILC3 from both CITE-seq and flow cytometry data of antigen presenting cells. Again, the pathogenic TH17 cell response to Hh remained relatively unaltered. Finally, to address whether the RORγt-expressing cells alone were sufficient to allow induction of Treg cells, the authors used irradiated congenic mice to deplete MHC class II expression on all CD11c-expressing cells and reintroduced MHC class II expression only on RORγt-expressing cells. They concluded that antigen presentation by these RORγt-expressing cells alone was sufficient to allow induction of Treg cells.

 

This study demonstrates that antigen presentation by ILC3s is required to promote Treg cell differentiation in response to Hh colonization. This provides additional support for the role of ILC3s in microbial antigen presentation and in directing the microbiome-specific adaptive immune response. If these findings in mice should be relevant to human disease, it is tempting to speculate that promoting antigen presentation by ILC3s might increase the number of Treg cells and thereby ameliorate intestinal inflammation in the context of inflammatory bowel disease.

  

Limitations

  • Lack of data demonstrating what effect T cell skewing had on impact of colitis

  • Applicability to other microbes needs to be determined

  • No attempt made to compare to human disease

Significance/Novelty

 

Confirmation that antigen presentation by type 3 innate lymphoid cells play a key role in skewing T cell responses towards a regulatory phenotype. 

 

Augmenting antigen presentation by this cell type may have a role in improving therapy in inflammatory bowel disease.

Credit

Reviewed by Rahul Ravindran as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM). Follow him on Twitter.