Identification and characterization of antigen-specific CD4+ T cells targeting renally expressed antigens in human lupus nephritis with two independent methods

AbstractIn the search for anti-renal autoreactivity in human lupus nephritis, we stimulated blood-derived CD4+ T cells from patients with systemic lupus erythematosus with various kidney lysates. Although only minor responses were detectable, these experiments led to the development of a search algorithm that combined autoantibody association with human lupus nephritis and target gene expression in inflamed kidneys. Applying this algorithm, five potential T cell antigens were identified. Blood-derived CD4+ T cells were then stimulated with these antigens. The cells were magnetically enriched prior to measurement with flow cytometry to facilitate the detection of very rare autoantigen-specific cells. The detected responses were dominated by IFN-γ-producing CD4+ T cells. Additionally, IL-10-producing CD4+ T cells were found. In a next step, T cell reactivity to each single antigen was independently evaluated with T cell libraries and [3H]-thymidine incorporation assays. Here, Vimentin and Annexin A2 were identified as the main T cell targets. Finally, Vimentin reactive T cells were also found in the urine of three patients with active disease. Overall, our experiments show that antigen-specific CD4+ T cells targeting renally expressed antigens arise in human lupus nephritis and correlate with disease activity and are mainly of the Th1 subset.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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T-Cell Reactivity to Polymorphic MHC Determinants II. Self-reactive and Self-restricted T Cells

Current Topics in Microbiology and Immunology - Specificity and Function of Clonally Developing T Cells ◽

10.1007/978-3-642-71152-7_31 ◽

1986 ◽

pp. 259-274 ◽

Cited By ~ 1

Author(s):

K. Heeg ◽

D. Kabelitz ◽

H. Wagner ◽

J. Reimann

Keyword(s):

T Cells ◽

T Cell ◽

Cell Reactivity ◽

T Cell Reactivity

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Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Hepatology ◽

10.1002/hep.24807 ◽

2012 ◽

Vol 55 (4) ◽

pp. 1130-1138 ◽

Cited By ~ 59

Author(s):

Stephen M. Brindley ◽

Allison M. Lanham ◽

Frederick M. Karrer ◽

Rebecca M. Tucker ◽

Andrew P. Fontenot ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Biliary Atresia ◽

Cell Reactivity ◽

T Cell Reactivity

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The RIG-I Agonist 3pRNA Synergizes with Checkpoint Blockade in Cancer Immunotherapy

Blood ◽

10.1182/blood.v126.23.3436.3436 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3436-3436 ◽

Cited By ~ 1

Author(s):

Simon Heidegger ◽

Diana Kreppel ◽

Michael Bscheider ◽

Alexander Wintges ◽

Sarah Bek ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Immunity ◽

Conflicts Of Interest ◽

Cytotoxic T Cells ◽

Type I ◽

Therapeutic Success ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Systemic Antibiotics

Abstract Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 has been shown to enhance anti-tumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination protocol that combines selective engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4-blockade. We found that vaccination together with RIG-I ligation strongly synergized with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells and potent anti-tumor immunity. Cross-priming of cytotoxic T cells as well as anti-tumor immunity required the adapter protein MAVS and type I interferon (IFN) signaling and were mediated by dendritic cells. In addition, the benefit of the combined immunization with anti-CTLA-4 was reduced by systemic antibiotics pointing to the requisite of an intact commensal microbiota in this context. Together, our findings describe a novel combinatorial strategy that may form the basis for the design of new type I IFN-based regimens that enhance antigen-specific T cell reactivity against cancer. Disclosures No relevant conflicts of interest to declare.

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Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

10.1101/2020.10.03.20206151 ◽

2020 ◽

Author(s):

Gennadi V. Glinsky

Keyword(s):

T Cells ◽

T Cell ◽

Herd Immunity ◽

Inverse Correlation ◽

Mortality Rates ◽

Virus Spread ◽

Cell Reactivity ◽

Cell Immunity ◽

Potential Impact ◽

T Cell Reactivity

AbstractSeveral recent studies identified SARS-CoV-2 reactive T cells in people without exposure to the virus. However, pathophysiological implications of these findings remain unknown. Here, the potential impact of pre-existing T cell reactivity against SARS-CoV-2 in uninfected individuals on markedly different COVID-19 mortality levels in different countries has been investigated. The inverse correlation is documented between the prevalence of pre-existing SARS-CoV-2 reactive T cells in people without exposure to the virus and COVID-19 mortality rates in different countries. In countries with similar levels of pre-existing SARS-CoV-2 cross-reactive T cells in uninfected individuals, differences in COVID-19 mortality appear linked with the extend and consistency of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing). Collectively, these observations support the model that the level of pre-existing SARS-CoV-2 reactive T cells is one of the important determinants of the innate herd immunity against COVID-19. Together with the consistent social measures directed to limit the virus spread, high levels of pre-existing SARS-CoV-2 reactive T cells appear significant determinants diminishing the COVID-19 mortality. Observations reported in this contribution should have significant impact on definitions of the herd immunity threshold required to effectively stop the pandemic in different countries across the globe.

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Interrogating CD8+ T cell reactivity on a genome-wide scale

Science Translational Medicine ◽

10.1126/scitranslmed.aaz0302 ◽

2019 ◽

Vol 11 (506) ◽

pp. eaaz0302

Author(s):

Kamila Naxerova

Keyword(s):

T Cell ◽

Large Scale ◽

Cd8 T Cell ◽

Cell Reactivity ◽

Human T Cell ◽

Genome Wide ◽

A Genome ◽

T Cell Antigens ◽

Wide Scale ◽

T Cell Reactivity

A new method enables large-scale identification of human T cell antigens.

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T Cell Reactivity to MHC Class II-Bound Self Peptides in Systemic Lupus Erythematosus-Prone MRL/lpr Mice

The Journal of Immunology ◽

10.4049/jimmunol.170.4.2229 ◽

2003 ◽

Vol 170 (4) ◽

pp. 2229-2235 ◽

Cited By ~ 11

Author(s):

Chang-Hee Suh ◽

John H. Freed ◽

Philip L. Cohen

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Mhc Class Ii ◽

Lupus Erythematosus ◽

Class Ii ◽

Systemic Lupus ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Self Peptides

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Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20050732 ◽

2005 ◽

Vol 202 (7) ◽

pp. 907-912 ◽

Cited By ~ 667

Author(s):

Luca Gattinoni ◽

Steven E. Finkelstein ◽

Christopher A. Klebanoff ◽

Paul A. Antony ◽

Douglas C. Palmer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Adoptive Cell Transfer ◽

Peripheral Tolerance ◽

Antitumor Efficacy ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Homeostatic Cytokines ◽

Cell Functionality

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γC cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

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