Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation

Abstract

Lymphocyte function in vivo is dictated by multiple external cues, but the integration of different signals is not well understood. Here, we show that competition for the axis of polarization dictates functional outcomes. We investigated the effect of ligation of the immunoregulatory cell surface receptor, CD46, on lymphocyte polarity during antigen presentation and cytotoxic effector function. Ligation of CD46 on human T cells prevented recruitment of the microtubule organizing center, CD3, and perforin to the interface with the antigen-presenting cell and caused a reduction in IFN-␥ production. In human NK cells, similar changes in polarity induced by CD46 ligation inhibited the recruitment of the microtubule organizing center and perforin to the interface with target cells and correlated with reduced killing. These data indicate that external signals can alter lymphocyte polarization toward antigen-presenting cells or target cells, inhibiting lymphocyte function.immunological synapse ͉ measles ͉ polar axis ͉ T cell signaling ͉ cytotoxicity L ymphocyte function is inf luenced by multiple extracellular cues, and the response to these signals is regulated by compartmentalization of proteins into distinct domains within the cell, for instance during migration or antigen presentation (1-3). Antigen presentation involves the formation of an immunological synapse (IS) proximal to the antigenpresenting cell (APC), remodeling of the actin and tubulin cytoskeletal networks, and clustering of signaling complexes at the distal pole of an axis perpendicular to the APC (4). Intracellular compartmentalization can control the sensitivity to signal, the duration of responsiveness to signal, and the direction of effector responses such as migration, cytotoxicity, and cytokine secretion (5). The signals that trigger polarization, such as ligation of chemokine receptors or the T cell receptor (TCR), are often modulated by the ensuing polarization state (2, 5), suggesting that cell polarity provides an inbuilt feedback mechanism.Recent reports suggest that extracellular signals compete to dictate both lymphocyte polarity and functional outcome. The intensity of signal from two target cells attached to the same T cell dictates the polarization of cytolytic granules (6). Competition between TCR and chemokine signaling determines whether a T cell adopts migratory polarization or forms an IS (7-9). To explore whether competition for polarization might provide a general means for controlling lymphocyte function, we investigated the effects of a competing polarizing signal on the response of lymphocytes to TCR or NK receptor signaling.CD46 is a cell surface receptor for complement C3b and a number of pathogens, including measles viruses (10 -12). CD46 ligation has been proposed to limit acquired immune function in response to complement and pathogens (12, 13) and facilitate the dramatic immunosuppression triggered by measles infection (14). Indeed, ligation of CD46 can mediate direct effects on T cell function, such as inducing regulat...

Abnormal Tr1 differentiation in multiple sclerosis

“…Enhanced proliferation was accompanied by drastic morphological changes of primary human T cells and actin relocalization (Zaffran et al, 2001), along with activation of Vav, critical for TCR activation and T cell activation-induced actin cytoskeleton rearrangements, as well as Rac activation, a GTPase of the Rho family. Such findings were reinforced by a recent report showing that CD46 modifies T cell and NK cell polarization (Oliaro et al, 2006). Of note, the functional orthologue of CD46 (that is not expressed in rodents) in rat or in mice (Crry) is also a costimulatory molecule for murine T cells (FernandezCenteno et al, 2000;Jimenez-Perianez et al, 2005), suggesting a new biological function for these complement regulatory molecules (Morgan et al, 2005).…”

Macropinocytotic Uptake and Infection of Human Epithelial Cells with Species B2 Adenovirus Type 35

“…The selection of CD46 as a receptor for numerous pathogens suggests that there are advantages for pathogens in binding to CD46, e.g., dampening or suppression of innate immune responses (43,76). The ubiquitously expressed human CD46 is involved in the control of complement lysis and inhibition of T-cell effector functions (6,44).…”

Downregulation of human CD46 by adenovirus serotype 35 vectors

“…Recently, CD46 has been demonstrated to be involved in not only complement regulation but also various cellular functions, such as immune responses. 37,38 It is essential to further examine the influence of surface CD46 downregulation, including the fate of the transduced cells, before initiating clinical applications of CD46-utilizing Ad vectors. Additionally, the influence of surface CD46 downregulation in vivo should be evaluated in nonhuman primates; the use of human CD46-transgenic mice is not recommended because rodent CD46 expression is limited in testis, and other complement regulators, such as decay-accelerating factor, protect cells from complement attack in rodents.…”