Tetramers reveal IL-17–secreting CD4⁺T cells that are specific for U1-70 in lupus and mixed connective tissue disease

Abstract

Antigen-specific CD4 + T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E k -containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4 + T-cell populations in MRL/lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine 140 . The frequency of CD4 + T cells specific for U1-70(131-150):I-E k (without phosphorylation) correlates with disease severity and anti-U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70-specific CD4 + T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4 + T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease.tetramer | autoimmunity | lupus | SLE | IL-17

Expanding the B Cell-Centric View of Systemic Lupus Erythematosus

“…For example, the study of Sm-reactive T cells in DR3 mice has uncovered a possible role of epitope mimicry in the activation of human autoreactive T cells [22]. In another example, activated CD4+ T cells secreting IL-17 and specific for the U1-70 antigen correlate with disease in a mouse model of lupus and a subset of SLE patients [23]. Some possible T cell epitopes could arise from post-translational modification of self-peptides, more frequent in inflammatory conditions.…”

Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution

“…The features on the microarrays represent overlapping peptides, with single-amino acid resolution in length and location, spanning amino acids 110–170 within the U1-70K RNA binding domain. We focused on the RNA binding domain, as it is the immunodominant autoantigenic region of U1-70K [12], and our lab recently identified a population of autoreactive CD4+ T cells in MRL/lpr mice specific for a peptide (131–150) within the region [25]. Further, a peptide-based therapeutic, rigerimod (IPP-201101, trade name Lupuzor), that features amino acids 131–151 of the U1-70K RNA binding domain is currently starting phase III clinical trials for treatment of SLE [26].…”

Emerging roles of the Th17/IL-17-axis in glomerulonephritis

“…In line with mouse model studies, sporadic IL-17 + CD3 + cells are found in the tubulointerstitial infiltrates in kidney biopsies from patients with active renal diseases [74]. A recent report identified IL-17-secreting CD4 + T cells that are specific for U1-70 in lupus using tetramer technology [75]. Additionally, single cell analyses from renal biopsies of patients with LuN by a laser microdissection technique revealed a positive correlation between percentage of IL-17 + TCR + cells within the kidney and hematuria and disease activity scores in LuN [76].…”