Multifaceted regulation of thymic tolerance by pattern recognition cascades

During their development, progenitor T cells have to pass through a series of tolerogenic filters inside the thymus, which ensure the survival and developmental advancement of only those thymocytes which fruitfully recognize the host’s own MHCs conjugated with non-self antigenic peptides. A set of microbial and host-derived biomolecules, called ‘patterns’, dynamically regulates the proficiency of this thymopoietic axis by a combination of thymocyte-extrinsic antigen presentation and thymocyte-intrinsic TCR signalling. Although well-characterized in terms of their impact on peripheral T cell tolerance, there is a lack of clarity regarding the influence of these patterns on the thymic tolerogenic checkpoints. From a clinical angle, this stands as a formidable weak point for the widely used immunosuppressive therapies against autoimmunity, which generically target these pattern recognition cascades. This review explores different aspects of the pattern recognition receptor-mediated regulation of key thymic events from an exclusively tolerogenic perspective, and unravels the mechanistic complexity underlying their impact on thymic tolerance. As the pattern recognition-mediated signalling cascades constitute a significant branch of the inflammatory network, inferences from this review elaborate a frequently overlooked collaboration between inflammation and self-tolerance; highlighting the need for potential therapeutic repurposing against autoimmune diseases.