A dormant T‐cell population with autoimmune potential exhibits low self‐reactivity and infiltrates islets in type 1 diabetes

Abstract

The contribution of low-affinity T cells to autoimmunity inthe context of polyclonal T-cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a result, lowaffinity T cells are often disregarded as nonantigen-specific cells irrelevant to the immune response. Our study aimed to assess how the level of self-antigen reactivity shapes T-cell lineage and effector responses in the context of spontaneous tissue-specific autoimmunity observed in NOD mice. Using multicolor flow cytometry in combination with Nur77 GFP reporter of TCR signaling, we identified a dormant population of T cells that infiltrated the pancreatic islets of prediabetic NOD mice, which exhibited reduced levels of self-tissue reactivity based on expression of CD5 and Nur77 GFP . We showed that these CD5 low T cells had a unique TCR repertoire and exhibited low activation and minimal effector function; however, induced rapid diabetes upon transfer. The CD4 + CD5 low T-cell population displayed transcriptional signature of central memory T cells, consistent with the ability to acquire effector function post-transfer. Transcriptional profile of CD5 low T cells was similar to T cells expressing a low-affinity TCR, indicating TCR affinity to be an important factor in shaping CD5 low T-cell phenotype and function at the tissue site. Overall, our study suggests that autoimmune tissue can maintain a reservoir of undifferentiated central memory-like autoreactive T cells with pathogenic effector potential that might be an important source for effector T cells during long-term chronic autoimmunity.

Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8+T cell pathogenicity in non-obese diabetic mice

“…In contrast to previous studies that compared TCR signaling in NOD and wild-type B6 mice (11), we investigate how thymic self-recognition impacts TCR signal strength and CD8 + T cell pathogenicity in NOD mice. Our research also differs from studies focusing on the CD4 + CD5 low T-cell population (12), which resembles central memory T cells and is linked to spontaneous autoimmunity in NOD mice. Instead, we find distinct TCR signal strength variations between CD5 hi and CD5 lo cells, with CD5 hi CD8 + cells showing enhanced activation, proliferation and disease transfer potential.…”

“…Therefore, the expression of CD5 is not only a surrogate marker for the strength of TCR-self-peptide-MHC interactions during development but also reflects the intrinsic response set point of T cells to a signal (5, 10). This selection process enriches the mature CD4 + T cell repertoire with clones that exhibit increased responses to self-peptide-MHC, thereby displaying enhanced peripheral immune responses to pathogens and autoantigens in vivo (5, 11, 12). Not only in CD4 + T cells, previous study has also shown that CD5 hi population in CD8 + T cells, characterized by higher reactivity to self-peptide-MHC, are prone to positive selection (5, 13).…”

Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection

“…Therefore, where are the reduced T cells going to come from? Kong et al showed that autoimmune tissue could maintain an undifferentiated central memory-like autoimmune Tcell pool, which has the potential for pathogenic effects and may be an important source of effector T cells during long-term chronic autoimmunity (73). It is worth mentioning that stem-like CD8+ T cells, effector CD8+ T cells and depleted CD8+ T cells can coexist in the pancreas of patients with TID (Figure 2).…”

“…Recent studies suggest that CD8+ stem-like T cells may play an important role in the pathogenesis of T1D. It has been found that effector T cells during long-term chronic autoimmunity may originate from an undifferentiated central memory-like autoimmune T-cell pool in autoimmune tissues, which contributes to the disease (73). T cells have the characteristics of stem cells and are an important cell type in the immune system.…”

MHC Class II Presentation in Autoimmunity

“…Low-affinity TCRs were also reported in the pathogenesis of T1D. The repertoire of the autoreactive T cells, infiltrating pancreatic islets, exhibited low self-reactivity and promoted the development of T1D [69]. Presumably, the interaction between these T1D TCRs and self-antigen-carrying pMHCs is also characterized by alternate topology.…”