108. CD4+ α3(135-145)-specific T cells in human Goodpasture Disease are enriched for Tscm and Th1 cells
Creators: name: Kate Robson1,2,5
name: Alikhan1, Maliha
name: Lim4, Jia Jia
name: Reid4, Hugh
name: Rossjohn4, Jamie
name: Richard Kitching1,2,3
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Goodpasture disease is defined by autoimmunity to the non-collagenous domain of the α3 chain of type IV collagen (α3(IV)NC1). Autoantibodies are readily measurable and central to the diagnostic algorithm. Antigen-specific cellular responses also have an important role in immunopathogenesis, but are difficult to assess in this and in other autoimmune diseases. This study defines the antigen-specific CD4<sup>+</sup> T cell population in blood from patients with Goodpasture disease. <strong>Methods:</strong> Peripheral blood samples were collected from 14 patients with Goodpasture disease at the time of first presentation, and isolated peripheral blood mononuclear cells (PBMCs) were assessed by flow cytometry. Antigen-specific cells were identified by staining with HLA-DR15 (DRA1*01:01/DRB1*15:01)-α3<sub>135-145</sub> tetramers, which identify cells specific to the immunodominant T cell epitope of α3(IV)NC1. CD4<sup>+</sup> T cell subpopulations and their chemokine receptor expression profiles were characterised with a surface stain panel comprising CD3, CD4, CD8, CD25, CD127, CD45RA, CCR7, CD95, CXCR3, CCR6, CCR4 and CXCR5. Nonparametric continuous paired variables were analysed by Wilcoxon signed rank test. <strong>Results:</strong> α3<sub>135-145</sub> specific cells were enriched in memory stem (CD45RA<sup>+</sup>CCR7<sup>+</sup>CD95<sup>+</sup>) T cells (Tscm) compared with the overall CD4<sup>+</sup> T cell pool (median % of conventional T cells 16.66% vs 5.32%, p=0.03), and comprised fewer naïve-like CD45RA<sup>+</sup>CCR7<sup>+</sup>CD95<sup>- </sup>cells (33.64% vs 50.24%, p=0.0001). A minority of α3<sub>135-145</sub>-specific CD4<sup>+</sup> cells were CD127<sup>lo</sup>CD25<sup>hi</sup> regulatory T cells (median 4.35%). A Th2 (CXCR3<sup>-</sup>CCR6<sup>-</sup>CCR4<sup>+</sup>) chemokine receptor expression profile was prominent across total and antigen-specific CD4<sup>+</sup> T cells. However, the α3<sub>135-145</sub>-specific population showed a significant skew towards T cells with effector function, specifically Th1 (CXCR3<sup>+</sup>CCR6<sup>-</sup>) polarisation (median % of antigen-experienced T cells 8.52% vs 2.74%, p=0.04), with a trend towards more Th17 (CXCR3<sup>-</sup>CCR6<sup>+</sup>) (9.55% vs 2.71%, p=0.07) and Th1/Th17 (CXCR3<sup>+</sup>CCR6<sup>+</sup>) (3.44% vs 0.15%, p=0.06) polarisation. <strong>Conclusions:</strong> Examination of the circulating CD4<sup>+</sup> α3<sub>135-145</sub>-specific T cell population implies a role for T cell-mediated autoimmunity in patients with Goodpasture disease, including long-lived Tscm cells (as described in rheumatoid arthritis and type 1 diabetes). Chemokine receptor expression profiles suggest that, in addition to Th2-mediated antibody responses, Th1- and potentially Th1/Th17 and Th17-polarised T cells are enriched in assessing antigen-specific T cell responses. <strong>Disclosures:</strong> None