TY - JOUR
T1 - Extrathymic AIRE-expressing cells
T2 - Friends or foes in autoimmunity and cancer?
AU - van Laar, Gustaaf G.
AU - van Hamburg, Jan Piet
AU - Tas, Sander W.
N1 - Funding Information: We are grateful for the funding through ReumaNederland (The Dutch Arthritis Foundation ) (grant 19-1-401 ). We thank the ear, nose and throat surgeons from the Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands, for collecting and providing tonsil tissue. Publisher Copyright: © 2022 The Authors
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Auto-immune regulator (AIRE) is a transcription factor that is mainly known for its crucial role in the thymus. Here, AIRE ensures central tolerance by promoting the expression of peripheral tissue antigens in thymic epithelial cells, which is essential for the negative selection of autoreactive T cells. Intriguingly, AIRE expressing cells have recently been identified in other tissues outside the thymus as well. However, the exact function of these extrathymic AIRE expressing cells (eTACs) remains largely enigmatic. Human eTACs are mainly found in secondary lymphoid tissues under homeostatic conditions, but are also found in pathologies such as the inflamed tissues of patients with autoimmune diseases and in various cancer tissues. eTACs have been demonstrated to express dendritic cell (DC)-like markers, such as MHCII, CD40 and CD127, but also CCR7, IDO and PD-L1. Interestingly, eTACs lack high expression of co-stimulatory molecules, such as CD80 or CD86. In mice, different types of peripheral AIRE expressing cells have been described, including cells with an innate lymphoid cell-like phenotype and antigen presenting cell (APC) function. These findings suggest that eTACs are APCs with the possibility to modulate or inhibit immune responses, which is confirmed by functional murine studies demonstrating the ability of eTACs to induce tolerance in autoreactive T cells. The potential immunomodulatory function of eTACs makes them promising targets to restore tolerance in autoimmunity or improve immunotherapy in cancer settings. Yet, this requires a better understanding of these cells and the molecular mechanisms involved. In this review we aim to summarize the current knowledge and understanding of eTACs, including their putative roles in health and disease.
AB - Auto-immune regulator (AIRE) is a transcription factor that is mainly known for its crucial role in the thymus. Here, AIRE ensures central tolerance by promoting the expression of peripheral tissue antigens in thymic epithelial cells, which is essential for the negative selection of autoreactive T cells. Intriguingly, AIRE expressing cells have recently been identified in other tissues outside the thymus as well. However, the exact function of these extrathymic AIRE expressing cells (eTACs) remains largely enigmatic. Human eTACs are mainly found in secondary lymphoid tissues under homeostatic conditions, but are also found in pathologies such as the inflamed tissues of patients with autoimmune diseases and in various cancer tissues. eTACs have been demonstrated to express dendritic cell (DC)-like markers, such as MHCII, CD40 and CD127, but also CCR7, IDO and PD-L1. Interestingly, eTACs lack high expression of co-stimulatory molecules, such as CD80 or CD86. In mice, different types of peripheral AIRE expressing cells have been described, including cells with an innate lymphoid cell-like phenotype and antigen presenting cell (APC) function. These findings suggest that eTACs are APCs with the possibility to modulate or inhibit immune responses, which is confirmed by functional murine studies demonstrating the ability of eTACs to induce tolerance in autoreactive T cells. The potential immunomodulatory function of eTACs makes them promising targets to restore tolerance in autoimmunity or improve immunotherapy in cancer settings. Yet, this requires a better understanding of these cells and the molecular mechanisms involved. In this review we aim to summarize the current knowledge and understanding of eTACs, including their putative roles in health and disease.
KW - Autoimmune regulator
KW - Autoimmunity
KW - Extrathymic AIRE-expressing cells
KW - Immunotolerance
KW - Malignancies
KW - Peripheral tolerance
UR - http://www.scopus.com/inward/record.url?scp=85134186159&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.autrev.2022.103141
DO - https://doi.org/10.1016/j.autrev.2022.103141
M3 - Review article
C2 - 35840039
SN - 1568-9972
VL - 21
JO - Autoimmunity Reviews
JF - Autoimmunity Reviews
IS - 9
M1 - 103141
ER -