A normal immune response is critical to protect humans against a variety of deleterious elements, including bacteria, viruses, and cancer cells. As a consequence, congenital immune deficiencies such as SCID (severe combined immunodeficiency) and acquired immune deficiencies such as AIDS can lead to greatly enhanced susceptibility to infections and cancers, which are associated with significant morbidity and mortality. Conversely, excessive immune responses can yield pathologies such as autoimmunity, which include type I diabetes, rheumatoid arthritis, lupus, and graft rejection.
Over the past 20 years, significant progress has been made toward understanding the molecular and biochemical basis of normal immunity. Most notable is our understanding of the mechanisms involved in “adaptive” immunity, which is mediated by the cells of the immune system known as T cells and B cells. These cells possess surface receptors that enable them to bind and react to specific “antigens.” The cells mount antigen-specific immune responses to viruses, parasites, fungi, and cancer cells but can also react with normal antigens found in the body, known as “self-antigens,” thereby causing autoimmune diseases. More recently, inroads have been made in elucidating the processes implicated in “innate” immunity, which involve cells such as natural killer cells, dendritic cells, and macrophages. While more rudimentary than T cells and B cells, these immune cells are crucial for initiating immune responses and protecting against viruses, bacteria, parasites, and cancer cells.
Our lab has had a longstanding interest in elucidating the molecular mechanisms by which immune cells are regulated. In the past, we discovered that CD4 and CD8, two important receptors expressed on T cells, are physically associated with an intracellular protein tyrosine kinase known as Lck. We found that Lck is implicated in the initiation of T cell activation by antigens. We demonstrated a similar role for FynT, another protein tyrosine kinase present in T cells, and found that Csk, a third protein tyrosine kinase, suppresses the activation of T cells as a result of its capacity to inactivate Lck and FynT. This function requires the association of Csk with the protein tyrosine phosphatase PTPN22/Lyp/PEP. Others have shown that mutations of PTPN22/Lyp/PEP that interfere with the ability to associate with Csk exist in humans with various types of autoimmune disease, including diabetes, rheumatoid arthritis, and lupus.
Our more recent work is aimed at assessing how alterations in the molecular mechanisms of immune cell activation, in particular those involving the SAP family of molecules, are implicated in human disease. SAP (SLAM-associated protein) is a small “adaptor” molecule that is expressed in cells of the immune system such as T cells, natural killer cells, and some B cells. It is mutated in X-linked lymphoproliferative (XLP) disease, an inherited human immunodeficiency that leads to a high frequency of infections and can cause cancers of the immune system. XLP patients are very sensitive to infection with the Epstein-Barr virus, which normally causes infectious mononucleosis but provokes exaggerated and sometimes fatal reactions in individuals with XLP. The patients also have a severely compromised ability to produce disease-fighting antibodies in response to viral infections. We and others have observed similar immune defects in mice that were genetically engineered to lack the SAP protein.
Over the past five years, we uncovered the mechanism by which SAP regulates the normal immune response. We found that SAP operates by recruiting the protein tyrosine kinase FynT to a group of receptors on immune cells referred to as the SLAM family of receptors. This discovery provided insights into the mechanisms by which SAP mutations may lead to immunodeficiencies in humans. We also revealed the function and mechanism of action of EAT-2, a molecule belonging to the same family as SAP but expressed in innate immune cells such as natural killer cells, dendritic cells, and macrophages. Natural killer cells are involved in killing cancer cells and cells infected with viruses. Interestingly, SAP and EAT-2 appear to have antagonistic functions in natural killer cells.
In the future, we will continue to study the role and regulation of the SAP protein in the various immune cell types where it is found, including T cells, B cells, and natural killer cells. We will strive to determine which of these immune cell types are directly implicated in SAP-dependent immune regulation in humans and mice and will assess whether SAP can work in the absence of the FynT kinase. In addition, we will examine in greater detail how EAT-2 regulates the normal immune response. Furthermore, we will ascertain whether alterations in EAT-2 are implicated in human diseases. Last, we will assess the roles of the various SLAM family receptors in controlling the activities of SAP and EAT-2 for normal immunity.
A better understanding of the molecular pathways controlling the immune response will continue to have a major impact on our ability to understand and, we hope, to treat human diseases such as immunodeficiency, autoimmunity, graft rejection, infection, and cancer.
Last updated July 2010
