Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Abstract

In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α+ DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α+ DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α+ DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α+ cDCs associated with increased percentages of CD4+ and CD8+ T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α+ DCs were also depleted. These results reveal that: 1) mTECs and CD8α+ DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α+ DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α+ DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα+ or plasmacytoid DCs.

Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance

“…Thymic cDC2 has been shown to be more efficient than cDC1 in presenting antigens acquired from circulation on MHC-II, and the appearance of cDC2 in the postnatal thymus coincides with an increased capacity for negative selection 67 . Furthermore, some studies using Batf3 − / − mice, which are deficient for cDC1, found that negative selection 21,29 and Treg induction 28,29 remained largely intact. Our imaging studies are consistent with these reports: the total contribution of AIRE + mTECs and cDC2 accounts for approximately two-thirds and three-quarters of the cellular contacts of activated OT-II CD4SP thymocytes in RIP-OVA hi and RIP-mOVA slices, respectively.…”

Rethinking Thymic Tolerance: Lessons from Mice

“…However, another study used other murine models of mTEC deficiency (Traf6DTEC mice), CD8a + cDC1 deficiency (Batf3 À/À mice), or Batf3 À/À Traf6DTEC doubleknockout mice to investigate, in comparison to wild-type mice, the interplay between these two thymic populations during tolerance induction. This study suggested that loss of both mTECs and cDC1 cells was required for loss of thymic tolerance, highlighting the ability of mTECs and DCs to partially compensate for one another to essentially prevent overt autoimmunity [42]. In line with this, investigations were made using autoimmune alymphoplasia aly/aly mice that harbor a point mutation in the NF-kB-inducing kinase (NIK) gene and suffer from absence of peripheral lymph nodes and Peyers patches.…”

Mechanisms of Tolerance Induction by Dendritic Cells In Vivo

“…Recently, it has been examined how mTECs and CD8α + -resident DCs contribute to thymic tolerance using mice depleted of mTECs and/or resident DCs ( 44 ). Although mice depleted of resident DCs were normal and those depleted of mTECs developed liver inflammation, depletion of both resident DCs and mTECs resulted in multiorgan autoimmunity.…”