Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

Giles, Josephine R.; Neves, Adriana Turqueti; Marshak‐Rothstein, Ann; Shlomchik, Mark J.

doi:10.1172/jci.insight.90870

Cited by 15 publications

(14 citation statements)

References 51 publications

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“…Importantly, although B cell–derived IL-6 is critical during this initial GC-dependent priming phase, autoreactive T cells likely sustain and propagate autoimmunity, via the production of IL-21 by cognate T FH cells and by the activation of additional naïve, autoreactive B cell clones, events which may occur independently of B cell TLR and, possibly, B cell–derived cytokine signals ( Giles et al, 2017 ). In addition, although direct interactions between autoreactive B cells and cognate CD4 + T cells are likely critical in this setting, B cell–derived IL-6 might also indirectly affect autoimmune GC formation, by, e.g., promoting the activation of DCs that facilitate T FH differentiation.…”

Section: Resultsmentioning

confidence: 99%

B cell–derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity

Arkatkar¹,

Du²,

Jacobs³

et al. 2017

Journal of Experimental Medicine

173

135

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Section: Resultsmentioning

confidence: 99%

B cell–derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity

Arkatkar¹,

Du²,

Jacobs³

et al. 2017

Journal of Experimental Medicine

173

135

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“…Genetic studies in families with rheumatic autoimmune diseases also support the initiating role of T cells in lupus (9), in addition to complement genes in the MHC locus (10). Importantly, augmented Th cell activity which is prevalent in lupus (11)(12)(13), can overcome the need for TLR abnormalities contributing to lupus (14). B cells and other professional APCs are activated to present autoantigens as the disease progresses.…”

Section: Introductionmentioning

confidence: 94%

Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future)

Datta

2021

Front. Immunol.

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Autoantigen-directed tolerance can be induced by certain nucleosomal histone peptide epitope/s in nanomolar dosage leading to sustained remission of disease in mice with spontaneous SLE. By contrast, lupus is accelerated by administration of intact (whole) histones, or whole nucleosomes in microparticles from apoptotic cells, or by post-translationally acetylated histone-peptides. Low-dose therapy with the histone-peptide epitopes simultaneously induces TGFβ and inhibits IL-6 production by DC in vivo, especially pDC, which then induce CD4+CD25+ Treg and CD8+ Treg cells that suppress pathogenic autoimmune response. Both types of induced Treg cells are FoxP3+ and act by producing TGFβ at close cell-to-cell range. No anaphylactic adverse reactions, or generalized immunosuppression have been detected in mice injected with the peptides, because the epitopes are derived from evolutionarily conserved histones in the chromatin; and the peptides are expressed in the thymus during ontogeny, and their native sequences have not been altered. The peptide-induced Treg cells can block severe lupus on adoptive transfer reducing inflammatory cell reaction and infiltration in the kidney. In Humans, similar potent Treg cells are generated by the histone peptide epitopes in vitro in lupus patients’ PBMC, inhibiting anti-dsDNA autoantibody and interferon production. Furthermore, the same types of Treg cells are generated in lupus patients who are in very long-term remission (2-8 years) after undergoing autologous hematopoietic stem cell transplantation. These Treg cells are not found in lupus patients treated conventionally into clinical remission (SLEDAI of 0); and consequently they still harbor pathogenic autoimmune cells, causing subclinical damage. Although antigen-specific therapy with pinpoint accuracy is suitable for straight-forward organ-specific autoimmune diseases, Systemic Lupus is much more complex. The histone peptide epitopes have unique tolerogenic properties for inhibiting Innate immune cells (DC), T cells and B cell populations that are both antigen-specifically and cross-reactively involved in the pathogenic autoimmune response in lupus. The histone peptide tolerance is a natural and non-toxic therapy suitable for treating early lupus, and also maintaining lupus patients after toxic drug therapy. The experimental steps, challenges and possible solutions for successful therapy with these peptide epitopes are discussed in this highly focused review on Systemic Lupus.

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“…As the retrovirus used in this assay is replication‐incompetent, the transduction procedure can be performed in a standard BSL‐2 tissue culture hood. So far, this method has been successfully applied to express more than 70 TCRs and has been used in over 20 publications in the past three years by multiple laboratories (Abraham et al., ; Bettini et al., ; Drobek et al., ; Giles, Neves, Marshak‐Rothstein, & Shlomchik, ; Gras et al., ; Guan et al., ; Guo et al., ; Jones, Alli, Li, & Geiger, ; Lee et al., ; Miao et al., ; Milasta et al., ; Ng, Leno‐Duran, Samanta, Almo, & Strominger, ; Packard et al., ; Snook et al., ; Sprouse et al., , ; Tan et al., ; Van Braeckel‐Budimir et al., ; Wolf, Emerson, Pingel, Buller, & DiPaolo, ; Yang et al., ). More recently, the method was adapted to express human TCRs in HLA‐humanized mice, which significantly expands the utility of the method in translational applications (Sprouse et al., ).…”

Section: Commentarymentioning

confidence: 99%

Generation of T Cell Receptor Retrogenic Mice

Kong

Bettini

2019

CP in Immunology

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The ability to express and study a single T cell receptor (TCR) in vivo is an important aspect of both basic and translational immunological research. Traditionally, this was achieved by using TCR transgenic mice. In the past decade, a more efficient approach for single TCR expression was developed. This relatively rapid and accessible method utilizes retrovirus‐mediated stem cell–based gene transfer and is commonly referred to as the TCR retrogenic approach. In this approach, hematopoietic bone marrow precursors are transduced with retroviral vector carrying both alpha and beta chains of a T cell receptor. After successful transduction, bone marrow is injected into recipient mice, in which T cell development is driven by expression of the vector‐encoded TCR. This article details the materials and methods required to generate TCR retrogenic mice. It is divided into three sections and provides detailed methods for generation of stable retroviral producer cell lines, isolation and optimal transduction of hematopoietic bone marrow cells, and subsequent analysis of TCR retrogenic T cells. A detailed example of such analysis is provided. The current protocol is a culmination of many years of optimization and is the most efficient approach to date. Bone marrow transduction and transfer into recipient mice can now be achieved in a short period of four days. The protocol can be followed in most laboratories with standard biomedical equipment, and is supported by a troubleshooting guide that covers potential pitfalls and unexpected results. © 2019 by John Wiley & Sons, Inc.

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Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

Cited by 15 publications

References 51 publications

B cell–derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity

B cell–derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity

Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future)

Generation of T Cell Receptor Retrogenic Mice

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