Peripheral tolerance

Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet⁺ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.

Exhausted T cells are associated with inefficient viral clearance, tumor immunity and response to immunotherapy. Here the authors show CD8⁺ T cells in the pancreatic islets have a LAG3-promoted ‘restrained’ phenotype resembling exhausted cells but maintain effector functions, and LAG3 expression limits pathology in the nonobese diabetic mouse model of type 1 diabetes.

Individuals with autoimmunity often have an increased frequency of T cells bearing features of follicular helper T cells in their blood. Lucy Walker proposes that alterations in pathways that regulate autoimmunity are coupled to alterations in follicular helper T cell homeostasis.

Pathways of glycan-mediated B cell suppression during pregnancy are important for promoting fetomaternal tolerance.

Follicular T cells regulate germinal centre reactions, but their phenotypes in autoimmune disease are unclear. Using a mouse model of autoantibody disease, the authors show that autoimmune follicular T cells differ by TCR clonotype and transcriptional profile from non-autoimmune follicular T cells.

Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host and inflammatory bowel disease. Here the authors identify a critical role for the alteration of the IEC-specific mitochondrial complex II component succinate dehydrogenase A in the regulation of the severity of T cell-mediated intestinal diseases.