Young AIREs go on to rule

Credit: Annaïck Guitteny Photography

Humans and mice with mutations in the autoimmune regulator (AIRE) gene develop a multi-organ autoimmune disease. The expression of AIRE during the first few weeks of life is necessary and sufficient to protect against the development of this disease. Reporting in Science, Yang et al. show that AIRE promotes the development of a distinct population of forkhead box P3 (FOXP3)-expressing CD4⁺ regulatory T cells (T_Reg cells) during the perinatal period and that these cells protect a specific set of tissues from autoimmune attack.

AIRE induces the promiscuous expression of peripheral tissue antigens in medullary thymic epithelial cells (mTECs), the processing and presentation of which is necessary for T cell selection. mTECs can positively select T_Reg cells in the thymus, so the authors first assessed the impact of AIRE deficiency on T_Reg cell development over time. They found that the percentage and the number of T_Reg cells were reduced in Aire^−/− mice compared with wild-type mice during the perinatal period.Furthermore, mice in which FOXP3⁺ T_Reg cells were conditionally depleted during the day 0–10 developmental window showed multi-organ autoimmune disease typical of Aire^−/− mice, even though normal T_Reg cell numbers were restored by day 11–12. The transfer of T_Reg cells from 20-day-old wild-type mice, but not from Aire^−/− mice, prevented disease development in these perinatally T_Reg cell-depleted mice. These data indicate that AIRE promotes the perinatal generation of T_Reg cells that protect against multi-organ autoimmune disease. Of note, the autoimmune disease that develops in the absence of AIRE is restricted to a limited set of tissues and is distinct from that which occurs in mice that constitutively lack T_Reg cells or mice in which T_Reg cells are depleted during adulthood.

To assess the phenotype and function of perinatally generated T_Reg cells, the authors used mice in which all FOXP3⁺ cells are marked with green fluorescent protein and a subset of cells that expressed FOXP3 at the time of tamoxifen administration are also marked with yellow fluorescent protein; in this study, tamoxifen was administered from days 0–10 ('perinatally tagged') or days 35–45 ('adult-tagged') after birth. Perinatally tagged T_Reg cells were shown to persist for at least 8 weeks after birth, although the percentage of these cells within the T_Reg cell compartment dwindled over this time as the total number of T_Reg cells exponentially increased.

perinatal T_Reg cells are functionally distinct from adult T_Reg cells

An analysis of the labelled T_Reg cells showed that perinatally tagged T_Reg cells: had higher transcription of genes associated with T_Reg cell effector function; performed better in an in vitro suppression assay; were more activated; and proliferated better than adult-tagged T_Reg cells. Furthermore, the transfer of perinatally tagged T_Reg cells, but not adult-tagged T_Reg cells, into newborn Aire^−/− mice prevented the development of the multi-organ autoimmune disease that typically occurs in these mice, which indicates that perinatal T_Reg cells are functionally distinct from adult T_Reg cells.

Further analysis identified age-dependent (but AIRE-independent) differences in the antigen processing and presentation machinery of mTECs, with ~50% of perinatal mTECs having low or no expression of CLIP (class II-associated invariant chain peptide), which occupies the peptide-binding groove of MHC class II molecules and must be dislodged to allow for peptide loading. Therefore, the repertoire of peptides presented by perinatal mTECs would be expected to be more diverse than adult mTECs. In addition, the T cell receptor repertoire of T_Reg cells from perinatal and adult mice was distinct.

AIRE promotes the perinatal development of a distinct population of T_Reg cells that protects a subset of tissues from autoimmune attack. However, further investigation is required to understand the link between AIRE and the age-dependent differences in antigen processing and presentation in mTECs and how this contributes to perinatal T_Reg cell development.