The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cellsin vitrofor clinical application, and summarize the recent progress of Tr1 cells in transplantation.

CD226 is known to be expressed on many types of peripheral lymphoid cells and involved in T cell differentiation, activation, and cytotoxicity. In this study, we report that CD226 is also expressed on mouse thymocytes at varying developmental stages, and its expression is associated with resistance of thymocytes to apoptosis. The levels of CD226 expression appeared to be closely coupled with thymocyte development, in that it was preferentially expressed on CD4⁺CD8⁻ and CD4⁻CD8⁺ thymocytes at all stages during mouse development, and was markedly increased on the cells in neonatal mice. Of the CD4⁺CD8⁺ population, CD226 was predominantly expressed by the cells also positive for CD69, suggesting that CD226 expression may be induced in thymocyte-positive selection. Inhibition of CD226 by short hairpin RNA in a fetal thymus organ culture model led to reduced thymus cellularity, which was associated with enhanced apoptotic cell death. In contrast, CD226-transgenic mice displayed enlarged thymus lobes resulting from increased thymus cellularity. CD226 on thymocytes seemed to play a role in regulating the expression of survivin, as inhibition of CD226 down-regulated survivin, but overexpression of CD226 rescued thymocytes from apoptosis through up-regulation of survivin. In addition, overexpression of CD226 reduced sensitivity of EL-4 thymoma cells to apoptosis by up-regulating the expression of survivin. Taken together, these results indicate that CD226 is an antiapoptotic molecule and may play an important role in murine thymocyte development.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a central and acute demyelinating disease of the central nervous system with unusual clinical course. The development of novel biomarkers for NMOSD is critical for implementing effective clinical treatment. CD226 is known to be expressed on many types of peripheral lymphoid cells. However, the expression level and function of CD226 on type 1 T regulatory (Tr1) cells during NMOSD is unknown.Methods: Eighteen patients with NMOSD and 10 healthy volunteers were enrolled in the test group to probe the difference of CD226 expression on Tr1 cells using flow cytometric analysis.Results: The expression of CD226 on Tr1 cells exhibited significantly increased tendency in NMOSD patients. Additionally, methylprednisolone and rituximab treatment decreased the expression of CD226 on Tr1 cells. Furthermore, the expression of CD226 on Tr1 cells was correlated with disease severity.Conclusion: This study provides a new basic insight into CD226 expression pattern on Tr1 cells, which have great potential to be biomarkers for monitoring the development and treatment of NMOSD.

Ulcerative colitis (UC) is a refractory and recurring inflammatory bowel disease (IBD). Monocytes and macrophages are major components of the mononuclear phagocyte system (MPS), and the balance between inflammatory monocytes and small peritoneal macrophages plays important roles in UC. However, the mechanisms governing the balance between inflammatory monocytes and small peritoneal macrophages in UC need to be clarified further. Here, we found that the expression levels of CD226 on different subsets of monocytes/macrophages are varied in UC mice. The expression levels of CD226 on patrolling monocytes (pMos) and small peritoneal macrophages (SPMs) were markedly increased, while the expression levels of CD226 on inflammatory monocytes (iMos) were decreased in UC mice. Significantly, the percentage of iMos was enhanced while the percentage of SPMs were decreased in CD226 knockout UC mice compared with that in wildtype UC mice. Moreover, CD226 deficiency suppressed the migration capacity of macrophages. Therefore, our data suggest that CD226 plays critical roles in regulating the function and balance of monocytes/macrophages in mouse UC and targeting CD226 in MPS may be developed as a potent therapy for UC.