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Co-inhibitory molecules: Controlling the effectors or controlling the controllers?
Govindarajan Thangavelu1, Christa Smolarchuk, Colin C Anderson
1Department of Surgery; Alberta Diabetes Institute; University of Alberta; Edmonton, Alberta Canada.
Insights
Co-inhibitory signals regulate immune responses by controlling T cells and innate immune cells. Understanding how these signals impact effector cells is crucial for developing new disease treatments.
Area of Science:
- Immunology
- Cellular Immunology
- Immune Regulation
Background:
- Co-inhibitory signals were proposed nearly 40 years ago to negatively regulate lymphocytes.
- Recent identification of co-inhibitors has propelled co-inhibition research.
- Co-inhibition is now understood to regulate both T cells and innate immune cells.
Purpose of the Study:
- To review the current understanding of co-inhibitory signals in immune regulation.
- To highlight the convergence of co-inhibition with regulatory T cell function.
- To emphasize the role of co-inhibition in innate immune cells.
Main Methods:
- Review of existing immunologic research on co-inhibitory signals.
- Analysis of data on the functions of identified co-inhibitors.
- Synthesis of information regarding co-inhibition in T cells and innate immune cells.
Main Results:
- Co-inhibitory signals directly regulate conventional T cells.
- Co-inhibitory signals converge with regulatory T cell-mediated negative control.
- Innate immune cells also express co-inhibitors and are regulated by them.
Conclusions:
- Co-inhibition is a critical mechanism for negative immune regulation.
- Future research should define conditions where co-inhibition controls effector cells intrinsically versus extrinsically.
- Understanding co-inhibition is key for developing novel therapeutic strategies for immune-related diseases.
Abstract:
Nearly forty years ago the concept was proposed that lymphocytes are negatively regulated by what are now called co-inhibitory signals. Nevertheless, it is only the more recent identification of numerous co-inhibitors and their critical functions that has brought co-inhibition to the forefront of immunologic research. Although co-inhibitory signals have been considered to directly regulate conventional T cells, more recent data has indicated a convergence between co-inhibitory signals and the other major negative control mechanism in the periphery that is mediated by regulatory T cells. Furthermore, it is now clear that lymphocytes are not the sole domain of co-inhibitory signals, as cells of the innate immune system, themselves controllers of immunity, are regulated by co-inhibitors they express. Thus, in order to better understand negative regulation in the periphery and apply this knowledge to the treatment of disease, a major focus for the future should be the definition of the conditions where co-inhibition controls effector cells intrinsically versus extrinsically (via regulatory or innate cells).
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