The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse (IS), with cellular or artificial APC, in a pattern we refer to as a "CD2 corolla". The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 costimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% compared to central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2 mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8 + tumor infiltrating lymphocytes displayed low expression of CD2 in the majority of colorectal, endometrial and ovarian cancer patients. CD2 down-regulation may attenuate anti-tumor T cell responses with implications for checkpoint immunotherapies.

During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.

The CD2 receptor has been described as an adhesion and costimulatory receptor on T cells. Here, transcriptional profiling of colorectal cancers (CRC) revealed a negative correlation between CD2 expression and "exhausted CD8 + Tcells" gene signatures. Furthermore, we detected reduced surface CD2 levels in exhausted CD127 low PD-1 hi CD3 + CD8 + tumour infiltrating lymphocytes (TILs) in CRC.We describe a CD2 expression-level-dependent switch in CD2-CD58 localization between central and peripheral domains in the immunological synapse (IS). A peripheral "CD2 corolla" formed when CD2 surface expression was sufficiently high and its cytoplasmic domain intact. The corolla recruited other ligated receptors like CD28, boosted recruitment of activated Src-family kinases (pSrc), LAT and PLC-γ in the IS and consequently T-cell activation in response to a tumour antigen. Corolla formation and pSrc in the IS increased linearly with CD2 expression, whereas pSrc signals were reduced by high, "exhausted-like" levels of PD-1, which invaded the corolla. These results suggest two levels of inhibition of Src-family kinases in CD3 + CD8 + TILs: reduced CD2 expression and high PD-1 expression.

No abstract

The physical problem under consideration is the boundary layer problem of an incompressible, laminar flow, taking place over a flat plate in the presence of a pressure gradient and radiation. For the mathematical formulation of the problem, the partial differential equations of continuity, energy, and momentum are taken into consideration with the boundary layer simplifications. Using the dimensionless Falkner–Skan transformation, a nonlinear, nonhomogeneous, coupled system of partial differential equations (PDEs) is obtained, which is solved via the homotopy analysis method. The obtained analytical solution describes radiation and pressure gradient effects on the boundary layer flow. These analytical results reveal that the adverse or favorable pressure gradient influences the dimensionless velocity and the dimensionless temperature of the boundary layer. An adverse pressure gradient causes significant changes on the dimensionless wall shear parameter and the dimensionless wall heat-transfer parameter. Thermal radiation influences the thermal boundary layer. The analytical results are in very good agreement with the corresponding numerical ones obtained using a modification of the Keller’s-box method.

Summary Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.

Amino acids and their metabolites are key regulators of immune responses, and plasma levels may change profoundly during acute disease states. Using targeted metabolomics, we evaluated concentration changes in plasma amino acids and related metabolites in community-acquired pneumonia (CAP, n = 29; compared against healthy controls, n = 33) from presentation to hospital through convalescence. We further aimed to identify biomarkers for acute CAP vs. the clinically potentially similar infection-triggered COPD exacerbation (n = 13). Amino acid metabolism was globally dysregulated in both CAP and COPD. Levels of most amino acids were markedly depressed in acute CAP, and total amino acid concentrations on admission were an accurate biomarker for the differentiation from COPD (AUC = 0.93), as were reduced asparagine and threonine levels (both AUC = 0.92). Reduced tryptophan and histidine levels constituted the most accurate biomarkers for acute CAP vs. controls (AUC = 0.96, 0.94). Only kynurenine, symmetric dimethyl arginine, and phenylalanine levels were increased in acute CAP, and the kynurenine/tryptophan ratio correlated best with clinical recovery and resolution of inflammation. Several amino acids did not reach normal levels by the 6-week follow-up. Glutamate levels were reduced on admission but rose during convalescence to 1.7-fold above levels measured in healthy control. Our data suggest that dysregulated amino acid metabolism in CAP partially persists through clinical recovery and that amino acid metabolism constitutes a source of promising biomarkers for CAP. In particular, total amino acids, asparagine, and threonine may constitute plasma biomarker candidates for the differentiation between CAP and infection-triggered COPD exacerbation and, perhaps, the detection of pneumonia in COPD.

During antigen recognition by T cells, a specific spatial structure is formed at the contact face to an antigen-presenting cell (APC), called an immunological synapse (IS). The IS supports bidirectional signaling and release of effector molecules and is widely studied both biologically and numerically, in order to understand the process of T cell activation and signaling. This specialized structure harbors a central area (central supramolecular activation cluster, cSMAC) populated by T cell receptor-peptide-major histocompatibility complex (TCR-pMHC ) interactions, hedged by a peripheral ring (peripheral supramolecular activation cluster, pSMAC) of integrin lymphocyte function associated-1 interactions with its immunoglobulin superfamily ligand intercellular adhesion molecule-1 (LFA-1-ICAM-1). These two regions form the "bull's eye" pattern characteristic of the mature IS.In theoretical studies, different modeling architectures, including partial differential equations (PDE) and agent-based models , have been developed with the purpose to answer mechanistic questions about the IS dynamics. In this chapter, we explain possible physiological mechanisms that lead to the formation of ISs and technical issues that may occur in the course of development of agent-based models.