Nuclear antigen–reactive CD4+ T cells expand in active systemic lupus erythematosus, produce effector cytokines, and invade the kidneys

Abdirama, Dimas; Tesch, Sebastian; Grießbach, Anna-Sophie; Spee-Mayer, Caroline von; Humrich, Jens Y; Stervbo, Ulrik; Babel, Nina; Meisel, Christian; Alexander, Tobias; Biesen, Robert; Bächer, Petra; Scheffold, Alexander; Eckardt, Kai‐Uwe; Hiepe, Falk; Radbruch, Andreas; Burmester, Gerd‐Rüdiger; Riemekasten, Gabriela; Enghard, Philipp

doi:10.1016/j.kint.2020.05.051

Cited by 32 publications

(28 citation statements)

References 37 publications

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“…This is comparable with past study demonstrating that untreated SLE patients had higher surface levels of gp130 on CD4 + T cells than inactive or stable SLE patients (47). Subsets of CD3 + CD4 + cells have been shown to be expanded in active SLE (48,49), and overactive or chronically active T cells are crucial in the pathogenesis of SLE (50,51). In addition, correlation with SLEDAI-2K scores was not observed in our cohort of patients when surface levels of IL-12Rb2 were taken into account i.e.…”

Section: Discussionsupporting

confidence: 90%

CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

et al. 2021

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The receptors for IL-35, IL-12Rβ2 and gp130, have been implicated in the inflammatory pathophysiology of autoimmune diseases. In this study, we set out to investigate the serum IL-35 levels and the surface levels of IL-12Rβ2 and gp130 in CD3+CD4+, CD3+CD4─ and CD3─CD4─ lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients (n=50) versus healthy controls (n=50). The potential T cell subsets associated with gp130 transcript (i.e. IL6ST) expression in CD4+ T cells of SLE patients was also examined in publicly-available gene expression profiling (GEP) datasets. Here, we report that serum IL-35 levels were significantly higher in SLE patients than healthy controls (p=0.038) but it was not associated with SLEDAI-2K scores. The proportions of IL-12Rβ2+ and gp130+ cells in SLE patients did not differ significantly with those of healthy controls in all lymphocyte subpopulations investigated. Essentially, higher SLEDAI-2K scores were positively correlated with increased proportion of gp130+ cells, but not IL-12Rβ2+ cells, on CD3+CD4+ T cells (r=0.425, p=0.002, q=0.016). Gene Set Enrichment Analysis (GSEA) of a GEP dataset of CD4+ T cells isolated from SLE patients (n=8; GSE4588) showed that IL6ST expression was positively associated with genes upregulated in CD4+ T cells vs myeloid or B cells (q<0.001). In an independent GEP dataset of CD4+ T cells isolated from SLE patients (n=9; GSE1057), IL6ST expression was induced upon anti-CD3 stimulation, and that Treg, TCM and CCR7+ T cells gene sets were significantly enriched (q<0.05) by genes highly correlated with IL6ST expression (n=92 genes; r>0.75 with IL6ST expression) upon anti-CD3 stimulation in these SLE patients. In conclusion, gp130 signaling in CD3+CD4+ T cell subsets may contribute to increased disease activity in SLE patients, and it represents a promising therapeutic target for inhibition in the disease.

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Section: Discussionsupporting

confidence: 90%

CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

et al. 2021

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“…Given the potential contribution of a SLE associated hyperresponsiveness, cells were also stimulated with the control antigen TTR and no differences in reactive cell numbers were detected. Using the same experimental set-up, previous work from our group also found no differences between active and inactive SLE patients and healthy controls upon stimulation with the recall antigen MP65 from candida albicans 31 .…”

Section: Discussionsupporting

confidence: 52%

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

Tesch

Abdirama

Grießbach

et al. 2020

Sci Rep

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In 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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“…Specifically, CD103+ TRM cells in the skin are positively correlated to disease severity and recurrence in patients. While TRM and T cell antigen specificities in lupus nephritis were recently described ( 52 , 53 ), specificities of skin autoreactive T cells are unknown. A trial blocking anti-IL-17 antibody for DLE is recruiting (NCT03866317).…”

Section: Trm In Vitiligomentioning

confidence: 99%

“…The T cell specificities in CLE skin are largely unknown, but SLE studies identified T cells reactive to nucleosomes/histones ( 59 ), which can induce anti-dsDNA antibody production ( 60 ). A recent study characterized antigen specificities of T cells in the kidney in lupus nephritis patients, and found that they recognize SmD1, RNP70, histone, Ro, La, and nuclear antigen ( 52 , 61 ). A population of CD8+ CD103+ tissue-resident memory T cells was identified and correlated positively with disease severity in patients ( 53 ).…”

Section: Trm In Cutaneous Lupus Erythematosusmentioning

confidence: 99%

Resident Memory T Cells in Autoimmune Skin Diseases

2021

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Tissue resident memory T cells (TRM) are a critical component of the immune system, providing the body with an immediate and highly specific response against pathogens re-infecting peripheral tissues. More recently, however, it has been demonstrated that TRM cells also form during autoimmunity. TRM mediated autoimmune diseases are particularly destructive, because unlike foreign antigens, the self-antigens are never cleared, continuously activating self-reactive TRM T cells. In this article, we will focus on how TRMs mediate disease in autoimmune skin conditions, specifically vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata and frontal fibrosing alopecia.

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Nuclear antigen–reactive CD4+ T cells expand in active systemic lupus erythematosus, produce effector cytokines, and invade the kidneys

Cited by 32 publications

References 37 publications

CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

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

Resident Memory T Cells in Autoimmune Skin Diseases

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