SIRPgamma: a novel checkpoint regulator of effector responses from human T-cells

点击翻译按钮获取中文摘要

Abstract A key unresolved question in immunology is: why do some individuals mount a balanced immune response that eliminates infection with no harm to host cells, whereas others have exaggerated immune responses that can cause significant tissue injury and precipitate autoimmunity? This question raises an unprecedented need to better understand the host mechanisms involved in fine-tuning immune responses in humans. T cells play a critical role in shaping a balanced immune response to antigens by directly recognizing molecules expressed on the cell surface and secreting factors that drive or dampen the inflammatory responses. Signal regulatory protein gamma (SIRP) is an immunomodulatory protein that is uniquely expressed on the cell surface of human T cells. Variants in the SIRPG gene have been associated with type 1 diabetes, relapsing remitting multiple sclerosis and maintaining a vaccine response long-term. However, how SIRP mechanistically contributes to inflammation remains unclear because we do not fully understand its function in the immune system. The overall goal of this research is to understand whether inter-individual differences in SIRP expression regulates the effector responses in human T cells. Previously we found that an autoimmunity risk variant in SIRP correlates with reduced expression of SIRP on the T-cells, and that T cells with less SIRP on the cell surface exhibit heightened effector status. This exciting discovery suggest that perturbations in SIRP levels may lead to immune dysregulation during infections and autoimmunity. To test this we will investigate whether intrinsic dysregulation in SIRP expression on naïve T cells accelerates their conversion into terminal effectors, thus driving hyper- proinflammatory responses. These studies will determine if SIRP plays a causative role in determining the magnitude and nature of effector responses from T cells. Given the association of SIRP with multiple autoimmune diseases and vaccine response, understanding the role of SIRP in immune regulation could significantly impact treatment in infection and autoimmunity.