Jovana Cupovic

B cell homeostasis and follicle confines are governed by fibroblastic reticular cells

Fibroblastic reticular cells (FRCs) are known to inhabit T cell–rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.

Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality

Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

Asymmetry of Cell Division in CFSE-Based Lymphocyte Proliferation Analysis

Flow cytometry-based analysis of lymphocyte division using carboxyfluorescein succinimidyl ester (CFSE) dye dilution permits acquisition of data describing cellular proliferation and differentiation. For example, CFSE histogram data enable quantitative insight into cellular turnover rates by applying mathematical models and parameter estimation techniques. Several mathematical models have been developed using different types of deterministic or stochastic approaches. However, analysis of CFSE proliferation assays is based on the premise that the label is halved in the two daughter cells. Importantly, asymmetry of protein distribution in lymphocyte division is a basic biological feature of cell division with the degree of the asymmetry depending on various factors. Here, we review the recent literature on asymmetric lymphocyte division and CFSE-based lymphocyte proliferation analysis. We suggest that division- and label-structured mathematical models describing CFSE-based cell proliferation should take into account asymmetry and time-lag in cell proliferation. Utilization of improved modeling algorithms will permit straightforward quantification of essential parameters describing the performance of activated lymphocytes.

Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell–dendritic cell interactions

Dendritic cell–derived thromboxane A2 (TXA2) limits T cell activation by inhibiting interactions between T cells and dendritic cells. Moalli et al., from the University of Bern, now show that the effect of TXA2 is selective for low-avidity T cells, perhaps as a way to boost the overall quality of immune responses.

Mathematical models for CFSE labelled lymphocyte dynamics: asymmetry and time-lag in division

Since their invention in 1994, fluorescent dyes such as carboxyfluorescein diacetate succinimidyl ester (CFSE) are used for cell proliferation analysis in flow cytometry. Importantly, the interpretation of such assays relies on the assumption that the label is divided equally between the daughter cells upon cell division. However, recent experimental studies indicate that division of cells is not perfectly symmetric and there is unequal distribution of protein between sister cell pairs. The uneven partition of protein or mass to daughter cells can lead to an overlap in the generations of CFSE-labelled cells with straightforward consequences for the resolution of individual generations. Numerous mathematical models developed so far for the analysis of CFSE proliferation assay incorporate the premise that the CFSE fluorescence intensity is halved in the two daughter cells. Here, we propose a novel modelling approach for the analysis of the CFSE cell proliferation assays which are characterized by poorly resolved peaks of cell generations in flow cytometric histograms. We formulate a mathematical model in the form of a system of delay hyperbolic partial differential equations which provides a good agreement with the CFSE histograms time-series data and allows an analytical treatment. The model is a further generalization of the recently proposed class of division- and label-structured models as it considers an asymmetric cell division. In addition, the basic structure of the cell cycle, i.e. the resting and cycling cell compartments, is taken into account. The model is used to estimate fundamental parameters such as activation rate, duration of the cell cycle, apoptosis rate, CFSE decay rate and asymmetry factor in cell division of monoclonal T cells during cognate interaction with dendritic cells.

Stromal Cell Niches in the Inflamed Central Nervous System

Inflammation in the CNS must be tightly regulated to respond efficiently to infection with neurotropic pathogens. Access of immune cells to the CNS and their positioning within the tissue are controlled by stromal cells that construct the barriers of the CNS. Although the role of the endothelium in regulating the passage of leukocytes and small molecules into the CNS has been studied extensively, the contribution of fibroblastic stromal cells as portals of entry into the CNS was only recently uncovered. We review the critical immune-stimulating role of meningeal fibroblasts in promoting recruitment and retention of lymphocytes during CNS inflammation. Activated meningeal fibroblastic stromal cells have the capacity to rapidly elaborate an immune-competent niche that sustains protective immune cells entering the CNS from the draining cervical lymph node. Such stromal cell niches can ultimately foster the establishment of tertiary lymphoid tissues during chronic neuroinflammatory conditions.

CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses

Background A particular characteristic of non–small cell lung cancer is the composition of the tumor microenvironment with a very high proportion of fibroblastic stromal cells (FSCs). Objective Lapses in our basic knowledge of fibroblast phenotype and function in the tumor microenvironment make it difficult to define whether FSC subsets exist that exhibit either tumor‐promoting or tumor‐suppressive properties. Methods We used gene expression profiling of lung versus tumor FSCs from patients with non–small cell lung cancer. Moreover, CCL19‐expressing FSCs were studied in transgenic mouse models by using a lung cancer metastasis model. Results CCL19 mRNA expression in human tumor FSCs correlates with immune cell infiltration and intratumoral accumulation of CD8+ T cells. Mechanistic dissection in murine lung carcinoma models revealed that CCL19‐expressing FSCs form perivascular niches to promote accumulation of CD8+ T cells in the tumor. Targeted ablation of CCL19‐expressing tumor FSCs reduced immune cell recruitment and resulted in unleashed tumor growth. Conclusion These data suggest that a distinct population of CCL19‐producing FSCs fosters the development of an immune‐stimulating intratumoral niche for immune cells to control cancer growth. Graphical abstract Figure. No Caption available.