Complement Activation Induces Excessive T Cell Cytotoxicity in Severe COVID-19

Georg, Philipp; Astaburuaga-García, Rosario; Bonaguro, Lorenzo; Brumhard, Sophia; Michalick, Laura; Lippert, Lena J; Kostevc, Tomislav; Gäbel, Christiane; Schneider, Maria; Streitz, Mathias; Demichev, Vadim; Gemünd, Ioanna; Barone, M.; Tober‐Lau, Pinkus; Helbig, Elisa T; Stein, Julia; Dey, Hannah-Philine; Paclik, Daniela; Mülleder, Michael; Aulakh, Simran Kaur; Mei, Henrik E.; Schulz, Axel; Hippenstiel, Stefan; Corman, Victor M.; Beule, Dieter; Wyler, Emanuel; Landthaler, Markus; Obermayer-Wasserscheid, Benedikt; Demir, Münevve; Wesselmann, Hans; Suttorp, Norbert; Uhrig, Alexander; Müller-Redetzky, Holger; Nattermann, Jacob; Kuebler, Wolfgang M.; Meisel, Christian; Ralser, Markus; Schultze, Joachim L.; Aschenbrenner, Anna C.; Thibeault, Charlotte; Kurth, Florian; Sander, Leif E.; Blüthgen, Nils; Sawitzki, Birgit

doi:10.2139/ssrn.3866835

Cited by 19 publications

(28 citation statements)

References 62 publications

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“…4C and Fig. S6), suggests that T cells acquire NK cell-like functional properties and antibody-dependent cytotoxicity within the lung tissue, in line with published reports 43 .…”

Section: Discussionsupporting

confidence: 90%

Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

Mothes

Pascual-Reguant

Koehler

et al. 2022

Preprint

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Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation.

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“…4C and Fig. S6), suggests that T cells acquire NK cell-like functional properties and antibody-dependent cytotoxicity within the lung tissue, in line with published reports 43 .…”

Section: Discussionsupporting

confidence: 90%

Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

Mothes

Pascual-Reguant

Koehler

et al. 2022

Preprint

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“…Recently, high-content single-cell technologies such as CyTOF and single-cell sequencing have allowed deep insights into the rich and previously unforeseen diversity of the phenotypic space of effector Th cells, which can cover the full spectrum between and around the conventional Th1, Th2, Th17 etc. cells (8,26,39,40). Furthermore, non-conventional Th cell phenotypes have been discovered for instance in the contexts of rheumatoid arthritis and tissue injury (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…A still unresolved question in Th cell differentiation is the lineage identity of mixed cell phenotypes such as Th1/2 hybrid cells. Those cells stably co-producing T-bet and GATA-3 have initially been discovered to arise in mouse models of parasite infections (7), their development was successfully recapitulated in vitro (7,17), and they are a common observation in recently available single-cell phenotyping data sets (8,26). Other non-conventional Th cells comprise Tfh-like PD-1 hi CXCR5 - , ‘peripheral helper’ T cells in rheumatoid arthritis (27), and Th17 cells in a ‘poised type 2 state’ in the context of tissue injury (28).…”

Section: Introductionmentioning

confidence: 99%

High-resolution kinetic gene expression analysis of T helper cell differentiation reveals a STAT-dependent, unique transcriptional program in Th1/2 hybrid cells

Burt

Peine

Borek

et al. 2022

Preprint

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Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo, and their generation could be reproduced in vitro. While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th cell differentiation into Th1, Th2 and Th1/2 hybrid cells. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ∼20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1 or Th2 cell gene expression, another fraction of ∼20% of genes followed a Th1 and Th2 cell-independent transcriptional program under control of the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes.

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“…Here, a non-lytic complement complex might form a synapse facilitating the deposition of immune complexes and subsequent signaling (60). Remarkably, CD16 + CD4 + and CD16 + CD8 + T EM cells (both with a cytotoxic phenotype and not T EMRA ) are strongly amplified in COVID-19 patients, their numbers correlating with severity of disease (65). The authors describe a complement-dependent – likely involving the complement receptors C3a and C3b – induction of CD16, upon which those adaptive T cells exert immune complex-mediated, TCR-independent cytotoxicity (65).…”

Section: Discussionmentioning

confidence: 99%

Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn’s Disease

Chiarolla

Schulz

Meir

et al. 2022

Preprint

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A complex and tissue-specific network of cells including T lymphocytes maintains intestinal homeostasis. To address disease and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with Crohn’s disease (CD) and healthy donor PBMCs. We compared inflamed and not inflamed tissue areas of bowel resections. Chronic inflammation enforced activation, exhaustion and terminal differentiation of CD4+ and CD8+ T cells and an enrichment of CD4+Foxp3+ cells (Tregs) in inflamed intestine. However, tissue-repairing Tregs decreased, while enigmatic rare Foxp3+ T-cell subsets appeared upon inflammation. In vitro assays revealed that those subsets, e.g. CD4+Foxp3+HLA-DR+TIGIT− and CD4+Foxp3+CD56+, express pro-inflammatory IFN-γ. Some T-conventional (Tcon) cells tended towards innateness. In blood of CD patients, not well studied CD4+ and CD8+ subsets of CD16+CCR6+CD127+ T cells appeared anew, a phenotype reproducible by incubation of healthy blood T cells with patient blood plasma. Together, these findings suggest a bias towards innate-like pro-inflammatory Tregs and innate-like Tcon, which act with less specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.Graphical Abstract

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Complement Activation Induces Excessive T Cell Cytotoxicity in Severe COVID-19

Cited by 19 publications

References 62 publications

Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

High-resolution kinetic gene expression analysis of T helper cell differentiation reveals a STAT-dependent, unique transcriptional program in Th1/2 hybrid cells

Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn’s Disease

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