Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity

Abstract

There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge.

Prédisposition aux pathologies auto-immmunes

“…Une déficience en AIRE est donc un moteur pour le développement de réactions auto-immunes : les lymphocytes T présentant une forte avidité et une autoréactivité peuvent être activés par les protéines du soi. Guerau-de-Arellano et al ont suggéré que l'expression de AIRE, durant une courte période correspondant à une fenêtre post-natale, était une condition nécessaire et suffisante pour permettre une tolérance efficace à long terme et ainsi éviter l'auto-immunité : le pool de lymphocytes T « tolérants » générés dans cette période pourrait contrecarrer les lymphocytes T autoréactifs susceptibles d'émerger par la suite [36]. La régulation de l'expression de AIRE par les hormones sexuelles au moment de la puberté renforce également la notion de fenêtre de temps de sensibilité dans la susceptibilité féminine aux pathologies auto-immunes (Figure 3).…”

Decreased AIRE Expression and Global Thymic Hypofunction in Down Syndrome

“…2). It would appear that an "autoimmune condition" is set at these early periods, the "compensation" that occurs later having little effect in correcting it (38). Clearly, not all DS patients present autoimmune disorders, although most show reduced AIRE expression (Figs.…”

Aire’s plant homeodomain(PHD)-2 is critical for induction of immunological tolerance

“…NOD/Lt J (Aire-WT) mice were originally purchased from the Jackson Laboratory. Aire-KO and iA-WT mice on the NOD genetic background have been described (19,27). An Aire cDNA carrying PHD2-domain deletion (amino acids 434-475) was constructed by QuikChangeII XL (Stratagene) and introduced into the ClaI site of the TOA construct (19).…”

“…An Aire cDNA carrying PHD2-domain deletion (amino acids 434-475) was constructed by QuikChangeII XL (Stratagene) and introduced into the ClaI site of the TOA construct (19). A fragment containing the Aire-ΔPHD2 cDNA intron and polyadenylation site from the rabbit β-globin gene were AatII and AfeI digested for the TOP construct, purified, and microinjected into NOD embryos as described (27). Progeny were screened by a PCR assay specific for the TOA and PHD2 transgene.…”

“…To address the function of Aire's PHD2 in vivo, we used a described system (26) to generate lines of transgenic mice expressing either WT Aire (iA-WT) or PHD2-deleted Aire (iA-ΔPHD2) quasi-specifically in thymic MECs, on an Aireknockout (Aire-KO) nonobese diabetic (NOD) background. Mice generated by using this system faithfully recapitulate the critical features of Aire control of immunological tolerance and have been used previously to examine the role of PHD1 in Aire's activities (19), as well as temporal aspects of Aire's impact on tolerance (27).…”