Signaling through CD43 regulates CD4 T-cell trafficking

Abstract

The mucin-like protein CD43 is excluded from the immune synapse, and regulates T-cell proliferation as well as T-cell migration. While the CD43 cytoplasmic domain is necessary for regulation of T-cell activation and proliferation, the mechanism via which CD43 regulates trafficking is not well defined. To investigate whether CD43 phosphorylation regulates its function in T cells, we used tandem mass spectrometry and identified Ser76 in murine CD43 as a previously unidentified site of basal phosphorylation. Interestingly, mutation of this single serine to alanine greatly diminishes T-cell trafficking to the lymph node, while CD43 exclusion and CD43-mediated regulation of T-cell proliferation remain intact. Furthermore, the CD43 extracellular domain was also required for T-cell trafficking, providing a hitherto unknown function for the extracellular domain, and suggesting that the extracellu- IntroductionCell-surface mucins, characterized by large, highly glycosylated extracellular domains, are important regulators of tumor progression as well as lymphocyte trafficking. 1 Overexpression and altered glycosylation of mucins on cancer cells, compared with normal cells, makes them ideal candidates for tumor-based vaccines. 2,3 CD43 is one such member of the mucin family, 4 and is widely expressed on the surface of hematopoietic cells. 5 Reduced expression and aberrant glycosylation of CD43 is found on the T cells of patients suffering from Wiskott-Aldrich syndrome, 6-8 as well as HIV infection. 9,10 In contrast, CD43 is overexpressed on lymphomas and leukemias, and while not normally expressed on nonhematopoietic cells, it is present on colon adenomas and carcinomas. 11,12 In spite of its abundance on T cells, the precise function of CD43 remains elusive. T cells from CD43 Ϫ/Ϫ mice exhibit increased proliferation and adhesion in vitro, 13,14 and increased immune responses in vivo. 15 Strikingly, CD43 is excluded from the immune synapse of activated T cells, 16 and often localizes to a protein complex distal to the antigen-presenting cell (APC) contact site, referred to as the distal pole complex (DPC). 17,18 Several groups have reported that failure to exclude CD43 results in inhibition of IL-2 production. 19,20 Based on these data, CD43 has been characterized as a negative regulator of T-cell function.The prevailing hypothesis to explain the mechanism of CD43-mediated negative regulation was that the CD43 extracellular domain acted as a barrier to cell-to-cell interactions. 13,[21][22][23] However, we and others have shown that the cytoplasmic domain is not only necessary, but also sufficient for movement of CD43 away from the immunologic synapse, as well as CD43-mediated attenuation of T-cell proliferation and homotypic adhesion. 14,17,20 These data underscore a critical function for the CD43 cytoplasmic tail in regulating T-cell proliferation and adhesion. Despite significant progress in elucidating the function of the CD43 cytoplasmic tail, there is no well-defined function for its extracellular domain. In the abs...

The Cleavage of Neutrophil Leukosialin (CD43) by Cathepsin G Releases Its Extracellular Domain and Triggers Its Intramembrane Proteolysis by Presenilin/γ-Secretase

“…46). Our data demonstrate a new function for cathepsin G, CD43 processing, which may be important for leukocyte migration, in view of CD43 known participation to leukocyte motility and trafficking (4,37,38).…”

“…Leukosialin, CD43, is the predominant cell surface sialoprotein of leukocytes (2) and has both anti-adhesive and adhesive properties. Its function has been mainly studied on lymphocytes, where CD43 behaves both as a negative regulator of T cell proliferation and adhesion and as a positive regulator of memory T cell trafficking (3,4). Although its expression is normally restricted to leukocytes, CD43 is present on colon carcinomas and on several nonhematopoietic cell lines (5,6).…”

“…CD43 has been recently described as a ligand for E-selectin (10,11). Its expression on polymorphonuclear neutrophils (PMN) is 10-fold higher than P-selectin glycoprotein ligand-1, PSGL-1, 4 the main leukocyte ligand for P-selectin, which also binds E-selectin. Despite CD43 abundance, data on its precise role in PMN responses are scarce.…”

P-Selectin Glycoprotein Ligand-1 Negatively Regulates T-Cell Immune Responses

“…In addition, the intracellular domain interacts with the adapter proteins ezrin and moesin (32,33), which function together to regulate T cell activation (34). The cytoplasmic domain of CD43 is also phosphorylated upon PMA stimulation (35). However, it remains unknown whether PSGL-1 and CD43 under physiological conditions bind to yet-undefined receptors to deliver an inhibitory signal for proliferation.…”

Common Polymorphisms in the CD43 Gene Region Are Associated with Tuberculosis Disease and Mortality

“…In addition to innate immune mechanisms, previous studies suggest that CD43 is involved primarily in three main functions: (1) cellular adhesion due to structural characteristics of the extracellular domain, which has O-glycosylated mucinlike aminoacids and sialic acid residues (39,40); (2) T cell activation and migration via cleavage of the CD43 extracellular domain, which interacts with endogenous lectin coreceptors (41) and proteins of the cytoskeleton (42) (CD43 uses E-selectin as a ligand on endothelial cells to regulate migration to sites of inflammation [41,43]); and (3) CD43 regulates T cell trafficking to lymph nodes via phosphorylation of a specific serine residue in the CD43 intracellular domain (42,44,45). Moreover, CD43 forms clusters via thiol group oxidation on lymphocytes.…”