IL-7 Dysregulation and Loss of CD8+ T Cell Homeostasis in the Monogenic Human Disease Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy

Abstract

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease that is caused by mutations in the AIRE gene. Murine studies have linked AIRE to thymocyte selection and peripheral deletional tolerance, but the pathogenesis of the human disease remains unclear. In this study, we show that APECED patients have elevated IL-7 levels and a drastically decreased expression of IL-7R on CD8+ T cells. This is associated with increased proliferation and a decreased expression of the negative TCR regulator CD5 in the CD45RO− subset. The CD45RO− cells also display oligoclonal expansions, decreased expression of the lymph node homing factors CCR7 and CD62L, and increased expression of perforin, consistent with the accumulation of highly differentiated effector cells. The CD45RO−CCR7+CD8+ population of cells with markers characteristic of naive phenotype is also skewed, as shown by decreased expression of CD5 and increased expression of perforin. The putative CD31+ recent thymic emigrant population is likewise affected. These data are consistent with IL-7 dysregulation inducing a decreased threshold of TCR signaling and self-antigen–driven proliferation, probably in synergy with the failed thymic selection. The resultant loss of CD8+ T cell homeostasis is likely to play a significant role in the pathogenesis of APECED. Our findings may also hold lessons for other diseases in which the IL-7–IL-7R pathway has emerged as a risk factor.

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

“…First, the Treg defect in APECED manifests already in recent thymic emigrants (27), strongly suggesting that its origins lay at least partly in abnormal thymic development. This skewed maturation of Treg is difficult to explain by increased responses to gut commensals, if for no other reason than that much of the thymic development precedes the establishment of normal flora.…”

“…Flow cytometric analysis of the patient cohort was done at the third sampling, and the phenotypic analysis of Treg and CD8 + T cells has been previously published (9,27); analysis of CD4 + cells has not been published. Briefly, PBMCs were isolated using Ficoll-Paque (GE Life Sciences, Little Chalfont, U.K.) gradient centrifugation and stained in a single step with directly conjugated mAb: CD4-allophycocyanin-Cy5, CD5-PerCP-Cy5.5, CD45RO-allophycocyanin (BD Biosciences, Franklin Lakes, NJ), CD8-Pacific Blue, CD25-PE-Cy7, CD31-PE-Texas Red, and CD127-allophycocyanin-Cy7 (eBioscience, San Diego, CA), although not all these markers are presented in the present study.…”

Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma

“…The patients have an increased frequency of highly differentiated CD45RA + CCR7 − effector/memory-like cells, which express the cytotoxic effector molecule perforin. Interestingly, the patients seem to have an almost complete lack of a normal naive CD8 + population since markers of aberrant activation are also found in CD8 + cells expressing markers associated with recent emigration from the thymus [12]. This may indicate that the cells are already activated in the thymus, as has been previously suggested [7].…”

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…The impaired thymic microenvironment of APECED patients is also indirectly reflected in the peripheral T cell compartment. A profound decrease in CD127 and CD5 surface marker expression and an almost complete lack of a conventional naïve T cell population (CD45RA + CD62L + CCR7 + perforin − ) were reported in APECED patients [147]. Importantly, recent thymic emigrants were also abnormal [147].…”