RESUMO
Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/fisiologia , Animais , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
CASE: A 12-year-old adolescent boy presented with a proximal fibula fracture and lateral ankle dislocation consistent with a Maisonneuve fracture (MF) associated with a transsyndesmotic ankle dislocation. The dislocation was reduced under conscious sedation in the emergency department. Postreduction imaging studies demonstrated a Tillaux fracture. The patient underwent surgical stabilization of the Tillaux fragment and of the distal tibiofibular syndesmosis. At the 26-month follow-up, the patient remained active without restrictions. CONCLUSION: Operative treatment of a concurrent MF, Tillaux fracture with lateral ankle dislocation, or a pediatric "logsplitter" injury resulted in satisfactory alignment and function of the ankle joint.