Transcriptional regulation and development of regulatory T cells

Regulatory T (Treg) cells are a distinct subset of CD4⁺ T cells. Instead of triggering adaptive immunity, they suppress immune responses. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Since they were first discovered 20 years ago, efforts have been made to understand the differences in developmental processes between Treg cells and conventional T cells that determine the ultimate fate of the overall T-cell population. Transcription factor Foxp3 is crucial for Treg cell differentiation, but it is not the whole story. Owing to recent advances in Treg cell research, we are now on the verge of appreciating the comprehensive mechanisms underlying Treg cell generation. Here, we discuss major discoveries, active study topics and remaining questions regarding Treg cell development.

Operative Treatment with Intramedullary Fibular Strut Allograft for Osteoporotic Proximal Humerus Fracture

BACKGROUND: The purpose of this study was to investigate the clinical and radiological outcomes of locking plate fixation with fibular strut allograft to manage unstable osteoporotic proximal humerus fractures. METHODS: We retrospectively reviewed 15 patients who underwent open reduction and locking plate fixation with fibular strut allograft for osteoporotic proximal humerus fracture between July 2011 and June 2015. For functional evaluation, we evaluated visual analogue scale (VAS) pain score, American Shoulder and Elbow Surgeons (ASES) score, University of California Los Angeles (UCLA) shoulder score, and active range of motion. For radiological evaluation, shoulder true anteroposterior (AP) and AP in 20° external rotation, as well as the axillary view were taken at two weeks, six weeks, three months, six months, and one year. And the neck-shaft angle was measured on the AP view in 20° external rotation view. RESULTS: At the one-year follow-up, mean VAS pain score and all shoulder scores, including ASES score and UCLA shoulder score, exhibited satisfactory clinical outcomes. All patients obtained bone union between three and six months post-procedure. Moreover, the mean immediate postoperative neck-shaft angle was 138°± 4°, and at one-year follow-up, the neck shaft angle was 137°± 5°. There was no significant difference between the preoperative and postoperative values (p=0.105). CONCLUSIONS: For the unstable two-part and three-part osteoporotic proximal humerus fractures with medial calcar comminution, the use of fibular strut allograft with locking plate fixation was effective in maintaining the initial status of reduction and exhibiting the satisfactory functional and radiological outcomes.

Casein kinase 2 is a critical determinant of the balance of Th17 and Treg cell differentiation

Th17 cells promote inflammatory reactions, whereas regulatory T (Treg) cells inhibit them. Thus, the Th17/Treg cell balance is critically important in inflammatory diseases. However, the molecular mechanisms underlying this balance are unclear. Here, we demonstrate that casein kinase 2 (CK2) is a critical determinant of the Th17/Treg cell balance. Both the inhibition of CK2 with a specific pharmacological inhibitor, CX-4945, and its small hairpin RNA (shRNA)-mediated knockdown suppressed Th17 cell differentiation but reciprocally induced Treg cell differentiation in vitro. Moreover, CX-4945 ameliorated the symptoms of experimental autoimmune encephalomyelitis and reduced Th17 cell infiltration into the central nervous system. Mechanistically, CX-4945 inhibited the IL-6/STAT3 and Akt/mTOR signaling pathways. Thus, CK2 has a crucial role in regulating the Th17/Treg balance.

The transcription factor Batf3 inhibits the differentiation of regulatory T cells in the periphery

Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells. The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells in vitro and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the Foxp3 locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation.

Operative Treatment with Intramedullary Fibular Strut Allograft for Osteoporotic Proximal Humerus Fracture

BACKGROUND: The purpose of this study was to investigate the clinical and radiological outcomes of locking plate fixation with fibular strut allograft to manage unstable osteoporotic proximal humerus fractures. METHODS: We retrospectively reviewed 15 patients who underwent open reduction and locking plate fixation with fibular strut allograft for osteoporotic proximal humerus fracture between July 2011 and June 2015. For functional evaluation, we evaluated visual analogue scale (VAS) pain score, American Shoulder and Elbow Surgeons (ASES) score, University of California Los Angeles (UCLA) shoulder score, and active range of motion. For radiological evaluation, shoulder true anteroposterior (AP) and AP in 20° external rotation, as well as the axillary view were taken at two weeks, six weeks, three months, six months, and one year. And the neck-shaft angle was measured on the AP view in 20° external rotation view. RESULTS: At the one-year follow-up, mean VAS pain score and all shoulder scores, including ASES score and UCLA shoulder score, exhibited satisfactory clinical outcomes. All patients obtained bone union between three and six months post-procedure. Moreover, the mean immediate postoperative neck-shaft angle was 138° ± 4°, and at one-year follow-up, the neck shaft angle was 137° ± 5°. There was no significant difference between the preoperative and postoperative values (p=0.105). CONCLUSIONS: For the unstable two-part and three-part osteoporotic proximal humerus fractures with medial calcar comminution, the use of fibular strut allograft with locking plate fixation was effective in maintaining the initial status of reduction and exhibiting the satisfactory functional and radiological outcomes.