Postdoctoral fellow Stanford University Stanford, California, United States
Disclosure(s):
Å imon Borna, PhD.: No financial relationships to disclose
Abstract Text: Immunedysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome is a prototypical primary immunoregulatory disorder caused by mutations in a FOXP3 gene, a transcriptional factor critical for the suppressive function of regulatory T cells (Treg). Atypical presentations of IPEX have recently increased the clinical variability and complicated the diagnoses. To facilitate early diagnoses and to better understand the disease's pathophysiological mechanisms, we studied the common molecular immune features of IPEX patients and the sources of autoreactive T cells. We identified a common Th-2 skewed cytokine profile in the patient's plasma and Th-2 skewed T cell phenotype. The epigenetic counting of immune cells showed expansion of the Treg compartment. Further studies of the IPEX’s expanded Treg cells indicated that they are unstable and adopt Th2 skewed Teff-like phenotype. Since Treg are physiologically self-reactive, the unstable Treg together with expanded autoreactive effector T cells, as indicated by TCR analyses, are representing the sources of the autoreactive T cells. The frequency of expanded unstable Treg seems to increase with disease severity and duration, sometimes preceding the clinical worsening of the disease. These data are crucial to complement the diagnosis by gene sequencing and monitor response to treatment. Currently, we are in phase I of CD4LVFOXP3 cell therapy, in which autologous IPEX T cells are converted to Treg-like cells by lentiviral-mediated FOXP3 expression. Understanding the heterogeneity of the cellular input for cell product manufacturing is a crucial step also for the development of Treg-based therapies.
Learning Objectives:
Analyses of T cell autoreactivity in prototypical autoimmune disease - tools, approaches and implications for therapy.
