Exploring the tolerogenic function of ct-CD45 on T cells

T cells play critical roles in host immune responses to pathogens. The activation and function of T cells are controlled by a multitude of extracellular signals in the form of soluble or membrane-bound ligands. Binding of these ligands to receptors on the surface of T cells is translated into intracellular signals that are processed in various ways inside the cell and determine the type, strength and termination of the response. CD45, the prototypic transmembrane protein tyrosine phosphatase (PTP), plays a central role in the processing of incoming signals into immune cell responses by regulating the phosphorylation status of protein tyrosine kinases. We have recently discovered that cytoplasmic tails of CD45 molecules (ct-CD45) are proteolytically cleaved and released upon activation of human phagocytes by fungi but not by other microbial stimuli. Most importantly, soluble ct-CD45 was found to act as an inhibitory, cytokine-like factor for T cells. Based on this initial study and our more recent findings, we want to define molecular mechanisms by which soluble ct-CD45 inhibits T cell activation and to determine whether the presence of ct-CD45 has clinical relevance. First we will investigate if protein associated with Toll-like receptor 4 (PRAT4A), which was recently identified by us as a candidate for the ct-CD45 receptor, is responsible for the inhibitory effects of ct-CD45 on human T cells. Then we will study the molecular and functional consequences of the inhibitory signal delivered by ct-CD45 to T cells, in particular induction of Schlafen12, a potential anergy factor. In the third part of our project we will examine the expression levels of ct- CD45 in patients with infectious diseases, in particular in cases with fungal infections, because ct-CD45 is detectable in the serum of patients with severe candidosis. Fungi, such as Candida albicans, are commensal microbes with effective strategies of immune evasion. Our previous findings suggest that fungi exploit this alternative function of CD45 as a novel mechanism of immune elusion. Thereby, ct-CD45 could represent not only a biomarker for fungal infections but also a potential target to fight fungal infections, particularly in immune-compromised patients. Moreover, due to the profound inhibitory effects on T cell proliferation, ct-CD45 could resemble a potential immunosuppressive agent for the treatment of autoimmune disease such as rheumatoid arthritis in the future.

T cells play a crucial role in the immune defense system. The activation and function of T cells is controlled by a variety of extracellular signals in the form of soluble and membrane-bound ligands. The binding of these ligands to receptors on the surface of T cells is translated into intracellular signals that are processed in the cell and determine the type, intensity and appropriateness of the immune response. Our group has now discovered that the cytoplasmic portion of CD45 receptors (ct-CD45) can be proteolytically cleaved by ?-secretase and released upon activation of human phagocytes. Interestingly, soluble ct-CD45 exerts an inhibitory function on T cells. In this project, the molecular mechanisms by which soluble ct-CD45 inhibits T cell activation have now been analyzed and we investigated the potential biological significance of ct-CD45 in humans within this project. The data obtained in this project demonstrate that ct-CD45 is present in human plasma of adults and contributes that T cells remain in the blood in a "resting state". In addition, we found that T cells activated in the presence of ct-CD45 are tolerized. Induction of Schlafen 12 (SLFN12) in T cells by ct-CD45 contributes to this hypo-proliferative state in T cells. SLFN12 leads to the inhibition of expression of cyclin D1, which is an important factor in cell cycle regulation of the early G1 phase. Thereby, ct-CD45-induced T cell anergy differs from classical T cell anergy, which blocks the cell cycle in the late G1 phase. Therefore, the results of our study show that the intracellular domain of CD45 from human phagocytes is a potent intercellular regulator of T cell activation. This novel mechanism of immune modulation could be the basis for a new, immune-suppressive agent for the treatment of autoimmune diseases such as rheumatoid arthritis. Moreover, ct-CD45 could serve as a biomarker for the diagnosis of inflammatory reactions.