Naïve arthritogenic SKG T cells have a defect in anergy and a repertoire pruned by superantigen

Abstract

How autoreactive CD4 T cells develop to cause rheumatoid arthritis remains unknown. We used a reporter for antigen-receptor signaling in the SKG autoimmune arthritis model to profile a T cell subpopulation enriched for arthritogenic naive CD4 T cells before arthritis onset by bulk and single cell RNA and T cell antigen-receptor (TCR) sequencing. Our analyses reveal that despite their impaired proximal TCR signaling, a subset of SKG naive CD4 T cells that have recently encountered endogenous antigen upregulate gene programs associated with positive regulation of T cell activation and cytokine signaling at higher levels than wild type cells in the pre-disease state. These arthritogenic cells also induce genes associated with negative regulation of T cell activation but do so less efficiently than wild type cells. Furthermore, their TCR sequences exhibit a previously unrecognized biased peripheral TCR Vβ repertoire likely driven by endogenous viral superantigens. These particular Vβs, known to recognize endogenous mouse mammary tumor virus (MMTV) superantigen, are further expanded in arthritic joints. Our results demonstrate that autoreactive naive CD4 T cells which recognize endogenous viral superantigens are poised to cause disease by their altered transcriptome.

NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*

“…7,12,44,49,50 As a result of sensitivity to not only strong stimulation, but also to weaker, sub-threshold, "tonic" antigen receptor signaling, Nr4a1 (as well as reporter GFP) is highly upregulated at the positive selection checkpoint during thymic selection, in selfreactive thymocytes destined for deletion, in Tregs, and in chronically antigen-stimulated anergic or exhausted T cells in mice and humans. 2,4,7,11,44,49,[51][52][53] Notably, reporter expression is also upregulated in autoreactive B cells in proportion to self-antigen recognition in vivo (Figure 1C). 7,12 Importantly, in T cells, reporter expression is not only a sensitive but also a specific marker of Ag stimulation 10,44,54 ; it has been shown that a range of inflammatory stimuli can induce activation marker expression in T cells, but fail to drive NUR77 upregulation.…”

“…Of particular importance, reporter (and endogenous Nr4a expression) is sensitive to “tonic” signaling in T and B cells in response to endogenous self‐antigen / pMHC in vivo 7,12,44,49,50 . As a result of sensitivity to not only strong stimulation, but also to weaker, sub‐threshold, “tonic” antigen receptor signaling, Nr4a1 (as well as reporter GFP) is highly upregulated at the positive selection checkpoint during thymic selection, in self‐reactive thymocytes destined for deletion, in Tregs, and in chronically antigen‐stimulated anergic or exhausted T cells in mice and humans 2,4,7,11,44,49,51‐53 . Notably, reporter expression is also upregulated in autoreactive B cells in proportion to self‐antigen recognition in vivo (Figure 1C).…”

“…NR4A transcripts have also been identified in B cells from RA joints and in peripheral blood B cells of SLE patients using both single‐cell and bulk sequencing technologies 63,64 . The upstream signals that drive transcript upregulation in these settings remain to be dissected, but single‐cell resolution has revealed that their expression marks cellular subsets with functional significance and may serve as powerful biomarkers in interrogating large data sets across immune‐mediated diseases 53,64 . Interestingly, despite these expression studies and their role in lymphocyte tolerance, common SNPs that influence NR4A expression or function have yet to be identified in association with human immune‐mediated disease.…”

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

“…Numerous viruses exist that cause cancer and inflammatory diseases modulated by genetic predisposition. In mice, we have discussed the comparison with MMTV, which is linked with breast cancer, lymphoma, and renal carcinoma, as well as autoimmune biliary disease, type 1 diabetes, and rheumatoid arthritis [53,89,138]. An example of analogous retrovirus infection in humans include HTLV-1 that leads to the development of adult T-cell leukemia/lymphoma in approximately 5% of infected individuals and other inflammatory/autoimmune diseases like HTLV-associated pulmonary disease and Sjögren's syndrome in a smaller proportion of patients [120,121].…”