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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Gene Expression Regulation/immunology , Homeostasis/immunology , Interleukin-7/immunology , Polyendocrinopathies, Autoimmune/immunology , Transcription Factors/immunology , Adult , Animals , Antigens, Differentiation/blood , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Child , Child, Preschool , Female , Gene Expression Regulation/genetics , Homeostasis/genetics , Humans , Interleukin-7/biosynthesis , Interleukin-7/genetics , Male , Mice , Middle Aged , Polyendocrinopathies, Autoimmune/blood , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/pathology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Interleukin-7/blood , Receptors, Interleukin-7/genetics , Receptors, Interleukin-7/immunology , Thymus Gland/immunology , Thymus Gland/metabolism , Thymus Gland/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , AIRE ProteinABSTRACT
The pathogenetic mechanisms of organ-specific autoimmune diseases remain obscured by the complexity of the genetic and environmental factors participating in the breakdown of tolerance. A unique opportunity to study the pathogenesis of human autoimmunity is provided by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare inherited autoimmune disease caused by mutations in Autoimmune Regulator (AIRE) gene. Loss of AIRE function disrupts the deletion of autoreactive T cells and impairs the suppressive function of regulatory T (Treg) cells. Here we show by multiparameter flow cytometry that in healthy controls the peripheral naive Treg cell subset forms a slowly dividing, persistent reservoir of recent thymic emigrants (RTEs). In APECED patients the RTE Treg cells show accelerated turnover and shift to the activated pool and the RTE reservoir is depleted. Moreover, the activated Treg cell population in the patients expresses significantly less Forkhead box protein P3 (FOXP3) than in the healthy controls, consistent with the impairment of peripheral activation. Our results indicate that in addition to their thymic effects, loss-of-function mutations in AIRE disrupt the peripheral homeostasis and activation of Treg cells. This may synergize with failed negative selection to cause APECED.
Subject(s)
Forkhead Transcription Factors/biosynthesis , Precursor Cells, T-Lymphoid/metabolism , T-Lymphocytes, Regulatory/metabolism , Transcription Factors/metabolism , Adult , Cell Separation , DNA Mutational Analysis , Down-Regulation , Female , Flow Cytometry , Forkhead Transcription Factors/genetics , Homeostasis , Humans , Lymphocyte Activation/genetics , Male , Middle Aged , Mutation/genetics , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Precursor Cells, T-Lymphoid/immunology , Precursor Cells, T-Lymphoid/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Transcription Factors/genetics , Transcription Factors/immunology , AIRE ProteinABSTRACT
In humans functionally mature FOXP3(+) regulatory T (Treg) cells can be found already in the fetus, but the kinetics of their maturation is still unknown. Here, we show that from birth to until 10 years of age the thymic production of FOXP3(+) Treg cells is very stable and correlates with T-lymphopoiesis in general. The level of FOXP3 expression in the blood was also very stable, even when children and adults were compared, but there was no correlation between thymic and peripheral FOXP3 levels. Analysis of the cell cycle-associated marker Ki67 showed that a substantial fraction of peripheral FOXP3(+) cells is dividing. This characteristic was obtained in the periphery, since it was not observed in thymic CD4(+) FOXP3(+) cells. These data suggest that the thymic output of human Treg cells is intrinsically stable, while in the periphery the increased rate of proliferation severs the connection between production and homeostatic maintenance of the FOXP3(+) Treg cell population.