The SAP family in immune regulationA normal immune response is critical to protect humans against a variety of deleterious elements, including bacteria, viruses and cancerous cells. As a consequence, congenital immune deficiencies such as SCID (severe combined immunodeficiency) or acquired immune deficiencies such as AIDS can lead to greatly enhanced susceptibility to infections and cancers, which are associated with significant morbidity and mortality. Moreover, excessive immune responses can yield pathologies such as auto-immunity, which include type I diabetes, rheumatoid arthritis and lupus, as well as graft rejection.
Over the past 20 years, significant progress has been made towards understanding the molecular and biochemical basis of normal immunity. Most notable is the comprehension of the mechanisms involved in “adaptive” immunity, which is mediated by 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”. They allow antigen-specific immune responses against viruses, parasites, fungi and cancer cells. They can also react with normal antigens found in the body, known as “self-antigens”, thereby causing auto-immune diseases. More recently, inroads have also 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 the initiation of immune responses and the protection against viruses, bacteria, parasites and cancer cells.
Dr. André Veillette has had a longstanding interest in elucidating the molecular mechanisms by which immune cells are regulated. In the past, he discovered that two important receptors expressed on T cells, CD4 and CD8, are physically associated with an intracellular enzyme known as the “protein tyrosine kinase” Lck. He and his team uncovered that Lck is implicated in the initiation of the activation of T cells by antigens. A similar role was demonstrated for FynT, another protein tyrosine kinase present in T cells. Dr. Veillette’s laboratory also 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 PTPN22/Lyp/PEP, an enzyme referred to as a ”protein tyrosine phosphatase”. Mutations of PTPN22/Lyp/PEP that interfere with the ability to associate with Csk were shown to exist in humans with various types of auto-immune diseases including diabetes, rheumatoid arthritis and lupus.
Dr. Veillette’s more recent work is aimed at assessing how alterations in 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 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 by Epstein-Barr virus, which normally causes infectious mononucleosis but provokes exaggerated and sometimes fatal reactions in individuals suffering from XLP. They also have a severely compromised ability to produce disease-fighting antibodies in response to viral infections. Similar immune defects were observed in mice that were genetically engineered to lack the SAP protein.
Over the past five years, Dr. Veillette’s laboratory uncovered the way by which SAP regulates the normal immune response. It found that SAP operates by recruiting the protein tyrosine kinase FynT to a group of receptors found 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. Dr. Veillette’s group also uncovered the function and mechanism of action of EAT-2, a molecule belonging to the same family as SAP but expressed in innate immune cells like natural killer cells, dendritic cells and macrophages. Natural killer cells are involved in the killing of cancer cells and cells infected by viruses. Interestingly, in natural killer cells, SAP and EAT-2 appear to have antagonistic functions.
In the future, Dr. Veillette and his team 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. They will strive to determine which of these immune cell types are directly implicated in SAP-dependent immune regulation in humans and mice. They will assess whether SAP can work in the absence of the FynT kinase. In addition, they will examine in greater detail how EAT-2 regulates the normal immune response. Furthermore, they will ascertain the possibility that alterations of EAT-2 are implicated in human diseases. Lastly, they will assess the respective roles of the various SLAM family receptors in controlling the activities of SAP and EAT-2 for normal immunity.
A better comprehension of the molecular pathways controlling the immune response will continue to have a major impact on our ability to understand and, hopefully, treat human diseases such as immunodeficiency, auto-immunity, graft rejection, infection and cancer.