Part of AIRE KO phenotype (APECED in humans) is dictated by gamma-delta T Cells

AIRE deficiency in mice (human equivalent of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) leads to chronic tissue immunopathology. Due to role of AIRE in generation of thymic FOXP3+ T regulatory cells, it is believed that underlying cause for tissue pathology on AIRE KO background is a lack of Tregs specific for tissue specific antigens.

However, the new data in journal Immunity from the research group which pioneered the study of AIRE suggest that part of AIRE KO phenotype is dictated by changes in γδ T cells secreting cytokine IL-17.

The authors observed that while total γδ T cells numbers were not different WT and AIRE KO littermates, γδ T cells expressing IL-17 were up-regulated in AIRE KO mice.

Interestingly, AIRE KO mice also deficient for γδ T cells (double deficient mice) showed marked resistance to immunopathology to such tissues as eyes and lungs (though other target tissues were still susceptible).

At the cellular level, there was a significant increase in IL-23r-GFP+ γδ T cells (marker for IL-17+ γδ+ T cells) in retinal tissue in AIRE KO mice at early age, even before tissue pathology was apparent. Of note, the fact that IL-17+ γδ+ T cells are present in retinal tissue in WT mice as well points to its role in physiological processes, not just in pathology).

In summary, this study indicates that subset of γδ T cells could play a leading role in initiating certain tissue pathology on AIRE KO background.

It is not clear, however, how changes in γδ T cell compartment relates to changes in Treg compartment on AIRE KO mice. Also, the role of tissue microbiota and its changes in KOs should be considered to fully understand immunopathologies. In this paper the authors provided the answers to neither to these two relevant topics.

David Usharauli

Remote control of tissue tolerance by regulatory T cells

This week journal PNAS published an interesting study on Foxp3+ regulatory T cells (Tregs). It showed that presence of Tregs within secondary lymphoid organs (in lymph nodes) was sufficient to prevent peripheral tissue immunopathology.

As a starting point for this study, the authors showed that mice with Tregs-specific deficiency of kruppel-like factor 2 (KLF2) develop non-fatal peripheral tissue immunopathology, even though in vitro such Tregs [Foxp3-cre; Klf2^fl/fl] displayed normal suppressive activity).

Interestingly, in vivo adoptive transfer model, KLF2-KO Tregs also failed to prevent colitis and weight loss when co-transferred with WT naive T cells [but not with KLF2-KO naive T cells].

These results suggested that Tregs re-circulation between tissue and lymphoid tissues could have been involved. Surprisingly, the authors found no difference for Tregs presence [%-wise, no data about #] between KLF2-KO mice or WT (this is probably why this article ended up in PNAS).

Finally, the authors showed that combined deficiency of KLF2 and CCR7 in Tregs accelerated tissue immunopathology [by preventing Tregs access to lymph nodes].

In summary, the authors speculated that Tregs access to lymphoid tissue played a crucial role in preventing tissue immunopathology.

David Usharauli