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Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D. Type 1 diabetes (T1D) manifests as hyperglycemia, with spontaneous remission occasionally observed, but the underneath mechanisms are unclear. Here the authors analyses patients at different stages to find two populations of immune cells correlating with disease progression or remission, while results from mouse diabetes models validate these observations. [ABSTRACT FROM AUTHOR]

This article follows the career of Saʿīd al-Shammākhī (d.1883), who served in Cairo, Egypt as the wakil of the Bey of Tunis from 1871–1881. I suggest that Shammakhi's life and career as wakil offers novel valence and voice to an increasingly polyvalent, polyphonic, and polychronic history of late Ottoman North Africa; namely, that of an Ibadi Muslim commercial and diplomatic agent, whose career linked two late-Ottoman Arab provinces at a decisive period in their history. The article situates Shammakhi in recent scholarship on late-Ottoman North Africa, with an emphasis on work that has sought to decenter European imperialism and colonialism as the defining factors in the chronology and history of the region. It also outlines his biography leading up to his appointment as wakil before then contextualizing Shammakhi's role as wakil by explaining the nature of that office. Shammakhi's time as wakil—and even the years following his death—expressed multiple belongings, imagined alternative futures past, and embodied a life and afterlife disrupted, but not defined, by the encounter between European imperialism and Ottoman lands in Africa. [ABSTRACT FROM AUTHOR]

A novel T cell-specific adaptor protein, RIBP, was identified based on its ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma library. RIBP was also found to interact with a related member of the Tec family of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural killer cells and is upregulated substantially after T cell activation. RIBP-disrupted knockout mice displayed apparently normal T cell development. However, proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)-mediated activation was significantly impaired. Furthermore, these activated T cells were defective in the production of interleukin (IL)-2 and interferon gamma, but not IL-4. These data suggest that RIBP plays an important role in TCR-mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may regulate T cell differentiation.

The T cell lineage–restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by Ptpn6), thereby dampening T cell antigen receptor (TCR) signaling and preventing the inappropriate negative selection of CD4+CD8+ thymocytes by positively selecting ligands. In contrast, in the SHP1 inhibition model, THEMIS is proposed to suppress SHP1 activity, rendering CD4+CD8+ thymocytes more sensitive to TCR signaling initiated by low-affinity ligands to promote positive selection. We sought to resolve the controversy regarding the molecular function of THEMIS. We found that the defect in positive selection in Themis−/− thymocytes was ameliorated by pharmacologic inhibition of SHP1 or by deletion of Ptpn6 and was exacerbated by SHP1 overexpression. Moreover, overexpression of SHP1 phenocopied the Themis−/− developmental defect, whereas deletion of Ptpn6, Ptpn11 (encoding SHP2), or both did not result in a phenotype resembling that of Themis deficiency. Last, we found that thymocyte negative selection was not enhanced but was instead impaired in the absence of THEMIS. Together, these results provide evidence favoring the SHP1 inhibition model, supporting a mechanism whereby THEMIS functions to enhance the sensitivity of CD4+CD8+ thymocytes to TCR signaling, enabling positive selection by low-affinity, self-ligand–TCR interactions. THEMIS shuts down SHP1 in thymocytes: In the thymus, the exposure of CD4 and CD8 double-positive (DP) thymocytes to self-peptide ligands that stimulate the T cell receptor (TCR) determines their fate. Insufficient TCR signaling results in death by neglect; excessive signaling leads to death by apoptosis to remove self-reactive cells; and sufficient signaling enables the positive selection of the thymocytes into CD4 or CD8 single-positive T cells. Mice deficient in the protein THEMIS exhibit failed thymocyte positive selection. Choi et al. showed that knockout of the inhibitory tyrosine phosphatase SHP1 reversed this defect in Themis knockout mice. Consistent with a model in which THEMIS inhibits SHP1 activity, overexpression of SHP1 phenocopied the effect of loss of THEMIS. In addition, DP thymocyte negative selection was impaired in the absence of THEMIS. Together, these findings suggest that THEMIS inhibits SHP1 in DP thymocytes to enhance their sensitivity to TCR stimulation by self-peptides. —JFF [ABSTRACT FROM AUTHOR]