NKT cell development in the absence of the autoimmune regulator gene (Aire)

Abstract

Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP3 1 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence selftolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.

AIRE deficiency leads to impaired iNKT cell development

“…Our mouse data is contradictory to a previous report on iNKT cells where no defect in iNKT cell development in absence of Aire was noted, except for a lower absolute number in the spleen of Aire À/À mice [14]. The reason for this discrepancy could be phenotypical differences between the Aire À/À mouse strains used in the two studies.…”

“…The Treg population develop in normal numbers and possess a normal phenotype and function in Aire À/À mice [5] whereas the function of CD4 þ CD25 þ Tregs from APS I patients is reported to be impaired [13]. Regarding the third major regulatory cell population, the iNKT cells, a previous mouse study concluded that the iNKT cell development is normal in Aire À/À mice with the exception of a decreased number of splenic iNKT cells [14]. In the human setting, the iNKT cells have not been investigated in absence of AIRE.…”

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

“…Extrathymic Aire-expressing cells have been shown to contribute to immune tolerance in secondary lymphoid organs (6) and both dendritic and NKT cell abnormalities have been reported in APECED (6,12,13,38). All of these cells have also been implicated in the regulation of intestinal immunity, so disruption of their function might promote loss of tolerance to commensal Ags.…”

Invariant natural killer T (iNKT) cell deficiency in chronic mucocutaneous candidiasis – A consequence or a cause?

“…Interestingly, Lindh et al recently reported that iNKT cell development was impaired in aire −/− mice and in 3 individuals with AIRE gene mutations [4]. In contrast, Pitt and colleagues showed that iNKT cell development is unimpaired in aire −/− mice [5] and Somech et al reported that children with Omenn syndrome have reduced transcriptional expression of the AIRE gene but normal iNKT cell frequency [6]. The reason for the discrepant findings is not clear.…”