Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

Abstract

The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount.DOI: http://dx.doi.org/10.7554/eLife.20616.001

Correcting the Mean-Variance Dependency for Differential Variability Testing Using Single-Cell RNA Sequencing Data

“…Additionally, we detect a heterogeneous up-regulation in the mRNA expression of the autocrine and paracrine growth factor IL-2 ( Il2 ) upon immune activation. This is in line with previous reports of binary IL-2 expression within a population of activated T cells, which has been suggested to be necessary for a scalable antigen response ( Fuhrmann et al., 2016 ). Heterogeneity in expression of these genes suggests that despite the uniform up-regulation of biosynthetic machinery, T cells in this early activation state represent a mixed population with varying degrees of activation and/or regulatory potential.…”

Robust expression variability testing reveals heterogeneous T cell responses

“…3C). This is in line with previous reports of binary IL-2 expression within a population of activated T cells (Bucy et al, 1994), which has been suggested to be necessary for a scalable antigen response (Fuhrmann et al, 2016). Heterogeneity in expression of these genes suggests that, despite their uniform up-regulation of biosynthetic machinery, the T cells in this early activation culture represent a mixed population with varying degrees of activation and/or regulatory potential.…”

“…Increased variability in Pou2f2 (Oct2) expression after activation suggests heterogeneous activities of the NF-»B and/or NFAT signalling cascades that control its expression (Mueller et al, 2013). Moreover, we detect up-regulated and more variable Il2 expression, suggesting heterogeneous IL-2 protein expression known to enable T cell population responses (Fuhrmann et al, 2016). This emphasizes the importance of variability detection in scRNAseq data.…”

The regulation of lymphocyte activation and proliferation

“…These experiments also highlight control of the second phase of the T cell response: Cytokines such as IL-2 and IL-4 play both a major role in initiating, as well as sustaining / extending cell division beyond their initial autonomous DD.This maintenance was shown to be particularly important for T cells that have migrated to sites of infection or inflamed tissue[14,15]. T cells modulate IL-2 production and integration of IL-2 signals as a mechanism of paracrine communication in order to fine tune and optimise the response magnitude[10,16,17]. Furthermore, although the proliferative effect of a particular stimulus can act predominantly on initial programming, it may also have alternate modulatory roles during the subsequent progression of the response.…”