Unveiling the Relevance of Immune Dysregulation in Disease Pathogenesis: the TR3-56 cell subtype as a Novel Immune- Regulatory Candidate

The immune system protects the body from infections and maintains overall health. This protection involves the activation of a complex process by which the immune response is triggered in response to the presence of pathogens (such as viruses, bacteria, fungi, etc.), foreign substances, or abnormal cells (e.g., cancer). This process, known as "immune activation", involves several cells and immune molecules working in harmony to defend against the pathological threats. Immune activation is expressed through the innate and adaptive immune responses, each with distinct roles and mechanisms for defending the body. The innate immune response acts rapidly as a first line of defence, providing immediate but relatively non-specific protection. It does not differentiate among specific pathogens but recognizes common characteristics shared by many, such as certain molecules on their surfaces. Components of the innate immune system include physical barriers like the skin and mucous membranes, as well as cellular and biochemical elements such as phagocytes (white blood cells that engulf and digest pathogens) and natural killer (NK) cells, which target infected or abnormal cells. The innate response often promotes pro-inflammatory phases and is itself triggered by inflammation, aiding in the recruitment of immune cells to infection sites and enhancing overall defence. The adaptive immune response develops more slowly but is highly specific, targeting particular pathogens and adapting to the microenvironmental conditions during the response. This response is characterized by "immunological memory," a fundamental feature of the adaptive immune system that offers a more effective response upon subsequent encounters with the same pathogen. Indeed, after encountering a specific pathogen, the adaptive immune system "remembers" it and responds more effectively to subsequent exposures. The adaptive response involves specialized white blood cells called B and T lymphocytes. B cells produce and secrete antibodies, which recognize and bind to specific antigens on pathogens, either directly neutralizing them or flagging them for elimination by other immune cells. T cells perform various functions, including assisting B cell functions (T helper, Th), directly killing infected cells (Cytotoxic T Lymphocytes, CTL), and regulating the immune response. The versatility of T cells is crucial for coordinating immune responses, adapting to different challenges, and ensuring an effective but controlled defence against infections and other threats. Therefore, immune activation is essential for defending the body against infections and other pathological threats. However, it is equally critical that this immune activation is followed by a “controlled shutdown” of the immune responses once the initial threat is neutralized. Without this regulation, prolonged immune activity can lead to unintended damage to the body's own cells, tissues, and organs, resulting in harmful autoimmune responses. This process is called “immune regulation” and plays a vital role in ensuring that the immune system recognizes and tolerates self-components, preventing auto-reactivity and the onset of autoimmune diseases. Therefore, a properly regulated immune system prevents both excessive immune reactions, which can lead to autoimmune diseases or insufficient responses, which can result in chronic infections or cancer. This regulatory process involves multiple mechanisms, including the suppression of overactive immune cells, the production of inhibitory cytokines, and the activation of regulatory cells, all of which are essential for maintaining immune homeostasis and protecting the body from self-inflicted damage. The main regulatory mechanisms involve immune cells such as regulatory T cells (Tregs), cytokines, and immune checkpoints, which ensure the proper “homeostasis of immune responses”. These elements act in synergy to prevent excessive or autoimmune reactions, ensuring a delicate balance between immune activation and immune tolerance. When these systems malfunction, it leads to dysregulation, contributing to various pathologies, including autoimmune disorders, chronic inflammation, and immune evasion by tumours. Understanding the factors that influence immunoregulation is essential for identifying therapeutic targets to treat immune-related diseases. This thesis explores the role of the novel candidate for immune-regulation, the TR3-56 cells, in four pathological models: the myelodysplastic syndromes (MDS), chronic lymphocytic leukaemia (CLL), COVID-19, and kidney transplantation, all of which involve balancing immune activation and regulation. The research during the PhD course has been highlighting TR3-56 involvement in immune regulation and disease determinism: i) these cells appear to contribute to immune dysregulation and disease progression by decreasing CTL activation and facilitating immune escape of myelodysplastic clones in MDS haematopoiesis; ii) Expansion of TR3-56 cells is correlated to immune evasion and leukemic spread in CLL, marking them as potential targets for new therapies; iii) Elevated TR3-56 levels in severe cases are associated with high CTL levels and inflammation in COVID- 19, suggesting their role in modulating immune responses during infections; iv) Increased TR3-56 levels correlate with unstable graft control in kidney transplantation, potentially serving as early indicators of immune-mediated graft issues. Overall, TR3-56 cells play a critical role in managing immune homeostasis and influencing disease outcomes, making them important for understanding and developing targeted therapies for these conditions. Therefore, the TR3-56 lymphocyte population emerges as a promising candidate for immune regulation. A deeper understanding of their role and functions may offer valuable insights into correcting immune imbalances, potentially making a significant impact in immunotherapy and disease management.