CD2 molecules redistribute to the uropod during T cell scanning: Implications for cellular activation and immune surveillance

Abstract

Dynamic binding between CD2 and CD58 counter-receptors on opposing cells optimizes immune recognition through stabilization of cell-cell contact and juxtaposition of surface membranes at a distance suitable for T cell receptor-ligand interaction. Digitized time-lapse differential interference contrast and immunofluorescence microscopy on living cells now show that this binding also induces T cell polarization. Moreover, CD2 can facilitate motility of T cells along antigen-presenting cells via a movement referred to as scanning. Both activated CD4 and CD8 T cells are able to scan antigen-presenting cells surfaces in the absence of cognate antigen. Scanning is critically dependent on T cell ␤-integrin function, as well as myosin light chain kinase. More importantly, surface CD2 molecules rapidly redistribute on interaction with a cellular substratum, resulting in a 100-fold greater CD2 density in the uropod versus the leading edge. In contrast, no redistribution is observed for CD11a͞CD18 or CD45. Molecular compartmentalization of CD2, T cell receptor, and lipid rafts within the uropod prearranges the cellular activation machinery for subsequent immune recognition. This ''presynapse'' formation on primed T cells will likely facilitate the antigen-dependent recognition capability required for efficient immune surveillance.A rrival of antigen-laden dendritic cells into the lymph node results in the activation of naive T cells, leading to their proliferation and acquisition of effector functions (1). The subsequent migration of activated T cells into pathogen-invaded body tissues is a key feature of immunity and immune surveillance. Diapedesis of T cells through the vascular endothelium, as well as their crawling movement on the surface of antigen presenting cells (APCs), parenchymal cells and extracellular matrix (ECM), requires T cell polarization (2). Although the molecular basis of this process is not well understood, certain features have been identified. Cell polarization is characterized by the formation of a leading edge at the front of the cell and a uropod at its back, allowing conversion of mechanical forces generated through adhesion to a substratum into net cellular locomotion (3). While the actin cytoskeleton redistributes at the leading edge, the microtubule organizing center (MTOC) localizes within the uropod allowing a greater deformability of the migrating cells (4-6). Given that the MTOC and the Golgi apparatus colocalize, the secretion of soluble mediators is directed toward the ligated cell surface (7). Moreover, chemokine receptors responsible for the directionality of the migration along a gradient of chemoattractants are concentrated within the leading edge (8). In contrast, the uropod mediates important adhesion functions, as suggested by accumulation of a notable number of adhesion molecules including ICAM-1, CD44, CD43, P-selective glycoprotein ligand 1 (PSGL-1), and L-selectin during migration (9, 10). The uropod therefore appears to anchor the cell to the ECM, APCs, or endothelial cells w...

Mechanosensing drives acuity of αβ T-cell recognition

“…57). T cells cluster their TCRs in the uropod, which is central to the cell and tied to actin structure undergoing retrograde flow (58,59). T cells exhibit frequent periods of persistent motion but with intermittent stops and turns.…”

“…3 and SI Appendix, Figs. S4 and S9) (59,60). Stresses were applied experimentally via loading through our optical trap system, delivering, on average, ∼10 pN per TCR-pMHC interaction.…”

Cha, a Basic Helix-Loop-Helix Transcription Factor Involved in the Regulation of Upstream Stimulatory Factor Activity

“…Additionally, USF overexpression has been found to inhibit growth in a number of cancer cell lines (27,28). USF-1 regulates CD2 expression in T cells (29) and is involved in such diverse functions as adhesion (30), scanning (31), activation (32,33), and positive/negative selection (34).…”

HIV-1 Entry into Renal Epithelia

“…The Joslin Clinic investigators noted that investigators at the Steno Memorial Hospital in Denmark reported a diminishing risk for ESRD over time in a similar group of patients with type 1 diabetes. 9,10 The factors responsible for this disparity are uncertain, although the pre-ESRD mortality in the Steno cohort was much higher than in the other two cohorts.…”

“…This interaction at the site of cell-to-cell contact is called a virologic synapse with polarized T cells forming a protrusion called uropod, which mediates contact with the other cell. 9,10 Chen et al, 11 in this issue of JASN, describe similar interactions between infected T cells and renal tubular epithelia. These investigators in their in vitro experimental model found viral transmission from infected T cells to renal tubular epithelial cells through cell-to-cell interaction, which they argue occurs through the formation of a virologic synapse.…”