The Roles of Checkpoint Inhibitors in Inflammatory Diseases

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Background

Immune checkpoints (also named co-inhibitory receptors) have evolved as regulators of the host’s protective immune responses to prevent the destruction of inflamed tissues. Activation of the immune system following pathogen encounter has to be counteracted to guarantee the resolution of inflammation without inflicting tissue damage. One mechanism to achieve this goal following immune cell activation is through modulation of the expression of co-inhibitory receptors on the cell surface of lymphocytes, such as programmed cell death protein-1 (PD-1), B and T lymphocyte attenuator (BTLA), CD160, T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), 2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM/CD150), lymphocyte activation gene 3 (LAG-3), or cytotoxic T cell associated protein 4 (CTLA4) on immune cells. Ligand binding to these co-inhibitory receptors, e.g. programmed cell death ligand 1 (PD-L1) or 2 (PD-L2), major histocompatibility complex II (MHC-II)/LSECTin, phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1), herpes virus entry mediator (HVEM), CD155/CD122, carcinoembryonic antigen-related cell adhesion molecule (CEACAM), CD48, or CD80/86 inhibits T cell function and modulates the course of the immune response. When an antigenic stimulus is present persistently in chronic inflammation, responsive cells become exhausted or die by apoptosis. Antigen-presenting cells and stromal cells express ligands for co-inhibitory receptors to prevent damage induced by T cell cytotoxic responses. This T cell subpopulation is essential to defend the host against virus-infected cells and tumor cells. Considering their mode of activation by antigens presented via the MHC class I complex, CD8+ T lymphocytes are consequently also major players in organ transplant rejection and autoimmune diseases. Therefore, the fine-tuned regulation of expression of co-inhibitory receptors as well as their corresponding ligands is a prerequisite for normal tissue homeostasis. Although being established as putative targets in anti-tumor therapy, its regulation remains elusive in inflammatory processes, in which a deeper knowledge may help us to design more effective strategies to treat these inflammatory processes.

Based on this proposed Research Topic, we aim to combine a selection of Original Research manuscripts and Review articles in the field of immune checkpoints focused on their role in the maintenance of normal tissue homeostasis and in the control of tissue inflammation. Submissions to this issue should clearly exclude the role of immune checkpoints in anti-tumor immune responses.

We welcome the submission of Review, Mini-Review and Original articles that cover, but are not limited, the following topics:

1. Inflammatory diseases associated with immune checkpoint dysfunction.
2. Expression profile of immune checkpoints and corresponding ligands in inflammatory diseases.
3. Molecular mechanisms involved in regulating the expression of immune checkpoints and their ligands.
4. Therapeutic approaches to circumvent immune checkpoint dysfunction and future perspectives.
5. Role of checkpoint inhibitors in inflammatory diseases.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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