Context matters: Molecular and cellular regulation of immune inhibitory receptor function

The immune system protects the body against pathogens such as bacteria, viruses, and parasites, and removes malignant cells such as cancer cells. It recognizes harmful cells and initiates responses to eliminate them. The immune system consists of different immune cell types, proteins, and organs that together form a highly advanced and complex network.

To prevent damage to the body, the immune system must be carefully regulated. Overactivation can cause inflammatory or autoimmune diseases, while insufficient activation increases the risk of infections and cancer. Immune inhibitory receptors (IIRs) help maintain this balance by controlling the start, duration, and strength of immune responses.

IIRs are also important targets for therapy. Some tumor cells escape immune attack by producing ligands that activate IIRs, suppressing the immune system. Cancer immunotherapy seeks to block IIRs so that tumor ligands can no longer inhibit immune cells. This strategy is very effective in some cancers but less so in others. Conversely, therapies that activate IIRs are being developed to suppress excessive immune activity in autoimmune and inflammatory diseases. A detailed understanding of how IIRs function is essential for these therapeutic approaches.

IIRs are transmembrane proteins with three parts: an extracellular domain that binds ligands, a transmembrane region, and an intracellular domain that transmits signals. These signals often rely on specific motifs, such as ITIM or ITSM, although some IIRs use other motifs.

This research investigated three IIRs: CD200R, PD-1, and LAIR-1.
• CD200R inhibits the immune system without ITIM or ITSM motifs. We wanted to know how CD200R then transmits signals. By comparing amino acid sequences of CD200R across species we found several overlapping amino acids. By changing these in human cells, we found that some of them are required for the inhibitory function of CD200R. Ultimately, we discovered a new and more extensive signaling motif: EEDExxPYxxYxxKxNxxY.
• PD-1, a major target in cancer immunotherapy, suppresses T cells when activated by tumor ligands. Blocking PD-1 can restore T-cell activity. We showed that inflammatory factors, especially interferon-alpha, reduced the effectiveness of PD-1 blockade in vitro. However, in a study of 22 melanoma patients, we found no link between inflammation levels and therapy outcomes.
• The outer parts of LAIR-1 and LILRB4 can bind to each other. We wanted to know what that means, so we studied their interaction. We found that LAIR-1 and LILRB4 do not act as ligands for each other when present on different cells. However, when expressed on the same cell, LILRB4 inhibits less effectively in response to the LILRB4 ligand in the presence of LAIR-1. This indicates that LAIR-1 disrupts the function of LILRB4 when they are present on the same cell.

Conclusion: The context in which an IIR functions is important for its effect. Their signaling motifs, interactions with inflammation, and influence on each other all shape their effects on the immune system. This knowledge is important for developing improved therapies for both cancer and autoimmune diseases.