Immune inhibitory receptors in viral infections and cancer

Summary

We are protected from external and internal dangers by our immune system. Immune responses need to be balanced to prevent uncontrolled inflammation and/or autoimmunity. Cell growth inhibition, apoptosis, and down regulation of receptor signals are all part of the inhibitory tools used by the immune system. Cells of the immune system have both activating and inhibitory receptors which can transmit positive and negative signals to the cells to keep the host immune system in balance. Immune inhibitory receptors are essential for the immune system during inflammation and help the system to move from uncontrolled circumstances to the controlled condition that returns the system to homeostasis. These inhibitors shape the magnitude, quality, and durability of immune responses. An expanding number of immune inhibitory receptors has been documented. In this thesis, two inhibitory receptors are studied: CD200 receptor (CD200R) and LAIR-1. Immune inhibitory receptors play an essential role in enforcing tolerance by managing various aspects of host defense mechanisms. Manyof the host and microbe immune-survival strategies turn out to be cellular intelligence versus invader intelligence. Balancing negative and positive signals is essential in limiting the damage caused by microbial infection on one hand, and inflammation on the other hand. Activating receptors are primed by conserved microbial patterns and through a cascade of reactions may lead to severe inflammation and eventually to pathology. Inhibitory receptors provide an indispensable help in fine tuning the exaggerated cellular responses in order to establish homeostasis. Most inhibitory receptors accomplish this by recruiting phosphatases through their cytoplasmic immunoreceptor tyrosine-based inhibition motif (ITIM). ITIM bearing receptors represent a growing family of receptors with inhibitory potential, which are expressed on most immune cells. Therapies that block inhibitory receptors are a major breakthrough in the context of cancer. This raises the question what the outcome of viral and bacterial infections would be during treatment with these blocking antibodies. Here we review the available data, focusing on different aspects of immune inhibitory receptors which optimize the host inflammatory response during infections. The important roles of inhibitory receptors in the prevention of immunopathology during infections are demonstrated in this review. As the field begins to better grasp how inhibitory receptors function individually and synergistically on distinct cell types, it may be possible to design more effective and specific therapeutic treatment strategies. Recent clinical trials with blocking antibodies against the inhibitory receptors CTLA4 and PD-1 have yielded promising results in therapeutic handles in anti-cancer treatment.The same mechanisms that restrain immune responses to prevent pathology from infection or autoimmunity could also be unfavourable for the elicitation of effective anti-tumor responses. Certainly blockade of inhibitory immune receptor pathways is recently developed as a novel therapy in cancer and has successfully entered clinical trials for development of therapeutic strategies.

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