T Cell Activation by TLRs: A Role for TLRs in the Adaptive Immune Response

Abstract Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a “dual effect” in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+ T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+ T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.

Download Full-text

Distinct immune responses in patients infected with influenza or SARS-CoV-2, and in COVID-19 survivors, characterised by transcriptomic and cellular abundance differences in blood.

10.1101/2021.05.12.21257086 ◽

2021 ◽

Author(s):

Jelmer Legebeke ◽

Jenny Lord ◽

Rebekah Penrice-Randal ◽

Andres F Vallejo ◽

Stephen Poole ◽

...

Keyword(s):

Immune Response ◽

T Cell Activation ◽

Cell Activation ◽

Topological Analysis ◽

Adaptive Immune Response ◽

Influenza Virus Infection ◽

The Body ◽

Nucleosome Assembly ◽

Bioinformatic Tools ◽

Adaptive Immune

Background The worldwide pandemic caused by SARS-CoV-2 has claimed millions of lives and has had a profound effect on global life. Understanding the pathogenicity of the virus and the body′s response to infection is crucial in improving patient management, prognosis, and therapeutic strategies. To address this, we performed functional transcriptomic profiling to better understand the generic and specific effects of SARS-CoV-2 infection. Methods Whole blood RNA sequencing was used to profile a well characterised cohort of patients hospitalised with COVID-19, during the first wave of the pandemic prior to the availability of approved COVID-19 treatments and who went on to survive or die of COVID-19, and patients hospitalised with influenza virus infection between 2017 and 2019. Clinical parameters between patient groups were compared, and several bioinformatic tools were used to assess differences in transcript abundances and cellular composition. Results The analyses revealed contrasting innate and adaptive immune programmes, with transcripts and cell subsets associated with the innate immune response elevated in patients with influenza, and those involved in the adaptive immune response elevated in patients with COVID-19. Topological analysis identified additional gene signatures that differentiated patients with COVID-19 from patients with influenza, including insulin resistance, mitochondrial oxidative stress and interferon signalling. An efficient adaptive immune response was furthermore associated with patient survival, while an inflammatory response predicted death in patients with COVID-19. A potential prognostic signature was found based on a selection of transcript abundances, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, in the blood transcriptome of COVID-19 patients, upon admission to hospital, which can be used to stratify patients likely to survive or die. Conclusions The results identified distinct immunological signatures between SARS-CoV-2 and influenza, prognostic of disease progression and indicative of different targeted therapies. The altered transcript abundances associated with COVID-19 survivors can be used to predict more severe outcomes in patients with COVID-19.

Download Full-text

Escherichia coli Prevents Phagocytosis-Induced Death of Macrophages via Classical NF-κB Signaling, a Link to T-Cell Activation

Infection and Immunity ◽

10.1128/iai.00138-06 ◽

2006 ◽

Vol 74 (10) ◽

pp. 5989-6000 ◽

Cited By ~ 14

Author(s):

Heinrich V. Groesdonk ◽

Silke Schlottmann ◽

Friederike Richter ◽

Michael Georgieff ◽

Uwe Senftleben

Keyword(s):

Escherichia Coli ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Inflammatory Responses ◽

Adaptive Immune Response ◽

Laboratory Strain ◽

Pyrrolidine Dithiocarbamate ◽

E Coli ◽

Adaptive Immune

ABSTRACT NF-κB is a crucial mediator of macrophage inflammatory responses, but its role in the context of pathogen-induced adaptive immune responses has yet to be elucidated. Here, we demonstrate that classical NF-κB activation delays phagocytosis-induced cell death (PICD) in Raw 264.7 and bone marrow-derived macrophages (BMDMs) upon ingestion of bacteria from the Escherichia coli laboratory strain Top10. By expression of a nondegradable form of IκBα (superrepressor) and pyrrolidine dithiocarbamate treatment, prolonged activation of NF-κB upon bacterial coculture is suppressed, whereas initial induction is only partially inhibited. This activation pattern results in partial inhibition of cellular activation and reduced expression of costimulatory CD86. Notably, suppression of classical NF-κB activation does not influence bacterial uptake rates but is followed by increased production of oxygen radicals and enhanced intracellular killing in Raw macrophages. This is associated with reduced expression of NF-κB-dependent antiapoptotic c-IAP-2 and a loss of the mitochondrial transmembrane potential. Accordingly, NF-κB inhibition in Raw cells and BMDMs causes increased apoptotic rates within 12 h of bacterial ingestion. Interestingly, accelerated eradication of E. coli in NF-κB-inhibited macrophages is associated with reduced antigen-specific T-cell activation in macrophage-lymphocyte cocultures. These data suggest that E. coli inhibits PICD of macrophages via classical, antiapoptotic NF-κB activation and thus facilitates signaling to T cells. Subsequently, a proper adaptive immune response is likely to be generated. Conclusively, therapeutic inhibition of classical NF-κB activation in macrophages may hamper the initiation of adaptive immunity.

Download Full-text

Regulation of peripheral T cell activation by calreticulin

Journal of Experimental Medicine ◽

10.1084/jem.20051519 ◽

2006 ◽

Vol 203 (2) ◽

pp. 461-471 ◽

Cited By ~ 29

Author(s):

Simona Porcellini ◽

Elisabetta Traggiai ◽

Ursula Schenk ◽

Denise Ferrera ◽

Michela Matteoli ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Adaptive Immune Response ◽

T Cell Response ◽

Mitogen Activated Protein Kinase ◽

Immunodeficient Mice ◽

Adaptive Immune ◽

The Impact

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt−/− hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt−/− T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.

Download Full-text

SARS-CoV-2 Human T cell Epitopes: adaptive immune response against COVID-19.

Cell Host & Microbe ◽

10.1016/j.chom.2021.05.010 ◽

2021 ◽

Author(s):

Alba Grifoni ◽

John Sidney ◽

Randi Vita ◽

Bjoern Peters ◽

Shane Crotty ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Adaptive Immune Response ◽

T Cell Epitopes ◽

Adaptive Immune ◽

Human T Cell

Download Full-text

IMGT® Biocuration and Comparative Analysis of Bos taurus and Ovis aries TRA/TRD Loci

Genes ◽

10.3390/genes12010030 ◽

2020 ◽

Vol 12 (1) ◽

pp. 30

Author(s):

Perrine Pégorier ◽

Morgane Bertignac ◽

Viviane Nguefack Ngoune ◽

Géraldine Folch ◽

Joumana Jabado-Michaloud ◽

...

Keyword(s):

Immune Response ◽

Comparative Analysis ◽

T Cell ◽

T Cell Receptors ◽

Bos Taurus ◽

Homo Sapiens ◽

Adaptive Immune Response ◽

Ovis Aries ◽

Cell Receptors ◽

Adaptive Immune

The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αβ and γδ, which express distinct TR containing either α and β, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine (Bos taurus) and the sheep (Ovis aries) have recently been described and annotated by IMGT® biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the Homo sapiens repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.

Download Full-text

Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy

The Journal of Immunology ◽

10.4049/jimmunol.0804018 ◽

2009 ◽

Vol 182 (12) ◽

pp. 8080-8093 ◽

Cited By ~ 135

Author(s):

Lachlan M. Moldenhauer ◽

Kerrilyn R. Diener ◽

Dougal M. Thring ◽

Michael P. Brown ◽

John D. Hayball ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Seminal Fluid ◽

Cross Presentation

Download Full-text

Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling

Cells ◽

10.3390/cells10040834 ◽

2021 ◽

Vol 10 (4) ◽

pp. 834

Author(s):

Frederike A. Hartl ◽

Jatuporn Ngoenkam ◽

Esmeralda Beck-Garcia ◽

Liz Cerqueira ◽

Piyamaporn Wipa ◽

...

Keyword(s):

T Cell ◽

Ligand Binding ◽

T Cell Activation ◽

Cell Activation ◽

Adaptor Protein ◽

Cooperative Interaction ◽

Tcr Signaling ◽

Binding Motifs ◽

Adaptive Immune

The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and the adaptor protein, Nck. Lck binds to a receptor kinase (RK) motif and Nck binds to a proline-rich sequence (PRS). Both motifs only become accessible upon ligand binding to the TCR and facilitate the recruitment of Lck and Nck independently of phosphorylation of the TCR. Mutations in each of these motifs cause defects in TCR signaling and T cell activation. Here, we investigated the role of Nck in proximal TCR signaling by silencing both Nck isoforms, Nck1 and Nck2. In the absence of Nck, TCR phosphorylation, ZAP70 recruitment, and ZAP70 phosphorylation was impaired. Mechanistically, this is explained by loss of Lck recruitment to the stimulated TCR in cells lacking Nck. Hence, our data uncover a previously unknown cooperative interaction between Lck and Nck to promote optimal TCR signaling.

Download Full-text

Abstract 442: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation in Angiotensin II (Ang-II)-dependent Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a442 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Heinrich E Lob ◽

Jiunn Song ◽

Scott D Butler ◽

Allyn L Mark ◽

Robin L Davisson

Keyword(s):

T Cell ◽

Er Stress ◽

T Cell Activation ◽

Cell Activation ◽

Adaptive Immune Response ◽

Fold Increase ◽

Peripheral Inflammation ◽

Ang Ii ◽

Peripheral Vascular ◽

Control Virus

The SFO is implicated in peripheral T cell activation and the genesis of Ang-II-dependent hypertension. Our recent studies show that ER stress in the SFO is also a key mechanism underlying the development of Ang-II hypertension. Because the ER is closely integrated with initiation of the adaptive immune response, we hypothesized that ER stress in the SFO contributes to peripheral inflammation in Ang-II hypertension. First, 5 days of intracerebroventricular (ICV) infusion of thapsigargin (Tg, 1 ug/day), a chemical ER stress inducer, caused a significant increase in CD3 + T cells in aortas (Tg: 11.9 ± 3.5 x 10 3 cells/aorta vs. Vehicle: 2.2 ± 0.7 x 10 3 cells/aorta , n = 6, p<0.05) and blood (Tg: 9.9 ± 1.8 x 10 4 cells/ mL vs. Vehicle: 2.9 ± 0.6 x 10 4 cells/ mL, n = 6, p<0.05). Furthermore, quantitative real-time PCR of SFO micropunches showed a 15-fold increase of TNF-α, a pro-inflammatory cytokine, a 3-fold increase of CCL5, a T cell attracting chemokine and a 3-fold increase in CD3, a T cell marker, (n = 4, p<0.05). To test the functional role of ER stress in the SFO in peripheral T cell activation, we targeted an adenovirus encoding GRP78 (AdGRP78), a molecular ER stress inhibitor, to this brain region during chronic systemic Ang-II infusion (600 ng/kg/min, 14 days). Our results demonstrate a significant reduction in T cell accumulation in aortas compared to control virus (AdLacZ) treatment (AdGRP78: 0.5 ± 0.07 x 10 4 cells/aorta vs. AdLacZ: 8.7 ± 2.1 x 10 4 cells/aorta, n = 6, p<0.05). These data show that 1) brain ER stress induces inflammation in the SFO and peripheral vascular T cell activation, and 2) ER stress in the SFO is linked to peripheral vascular T cell activation in Ang-II-dependent hypertension. These results suggest that ER stress and inflammation in the SFO induce peripheral vascular T cell activation and inflammation in Ang-II hypertension.

Download Full-text

Megakaryocyte derived immune-stimulating cells regulate host-defense immunity against bacterial pathogens

10.1101/2021.06.09.447810 ◽

2021 ◽

Author(s):

Jin Wang ◽

Jiayi Xie ◽

Xue Han ◽

Daosong Wang ◽

Minqi Chen ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Bacterial Infection ◽

Host Defense ◽

T Cell Activation ◽

Cell Activation ◽

Hematopoietic Stem ◽

Bacterial Response ◽

Stem Cell Quiescence ◽

Express Cell

Megakaryocytes (MKs) continuously produce platelets in bone marrow to support hemostasis. However, MKs also play roles beyond thrombopoiesis as they regulate hematopoietic stem cell quiescence and erythropoiesis, which suggests the functional heterogeneity of MKs. Here, using single-cell sequencing we identified an MK-derived immune-stimulating cell (MDIC) population, which plays an important role in host-protective response against bacteria. In contrast to platelet-generating MKs, MDICs highly express cell migration, immune-modulatory, and response genes. Upon Listeria (L.) monocytogenes infection, MDICs egress to circulation and infiltrate into the spleen, liver and lung. MDICs interact with myeloid cells to promote their migration and tissue infiltration. More importantly, MDICs stimulate phagocytosis of macrophages and neutrophils by producing TNFα and IL-6 and facilitating antigen-specific T cell activation via IL-6 to enhance anti-bacterial response. Ablation of MKs reduced innate immune response and compromised T cell activation in spleen and liver, impairs the anti-bacterial effects in mice under L. monocytogenes challenge. Finally, infection-induced emergency megakaryopoiesis efficiently stimulated MDICs generation upon bacterial infection. Overall, we identify MDICs as a novel MK subpopulation, which regulates host-defense immune response against bacterial infection.

Download Full-text