Mechanisms of Direct and Indirect Presentation of Self-Antigens in the Thymus

Abstract

The inevitability of evolution of the adaptive immune system with its mechanism of randomly rearranging segments of the T cell receptor (TCR) gene is the generation of self-reactive clones. For the sake of prevention of autoimmunity, these clones must be eliminated from the pool of circulating T cells. This process occurs largely in the thymic medulla where the strength of affinity between TCR and self-peptide MHC complexes is the factor determining thymocyte fate. Thus, the display of self-antigens in the thymus by thymic antigen presenting cells, which are comprised of medullary thymic epithelial (mTECs) and dendritic cells (DCs), is fundamental for the establishment of T cell central tolerance. Whereas mTECs produce and present antigens in a direct, self-autonomous manner, thymic DCs can acquire these mTEC-derived antigens by cooperative antigen transfer (CAT), and thus present them indirectly. While the basic characteristics for both direct and indirect presentation of self-antigens are currently known, recent reports that describe the heterogeneity of mTEC and DC subsets, their presentation capacity, and the potentially non-redundant roles in T cell selection processes represents another level of complexity which we are attempting to unravel. In this review, we underscore the seminal studies relevant to these topics with an emphasis on new observations pertinent to the mechanism of CAT and its cellular trajectories underpinning the preferential distribution of thymic epithelial cell-derived self-antigens to specific subsets of DC. Identification of molecular determinants which control CAT would significantly advance our understanding of how the cellularly targeted presentation of thymic self-antigens is functionally coupled to the T cell selection process.

Single-cell transcriptomics reveals heterogenous thymic dendritic cell subsets with distinct functions and requirements for thymocyte-regulated crosstalk

“…Cd36 , a scavenger receptor that facilitates acquisition of cell-surface proteins from apoptotic mTECs 45 , is expressed exclusively by cDC1 subsets (Fig. 1b), indicating that cDC2s must use alternative mechanisms to acquire mTEC-derived antigens, possibly via trogocytosis, exosome transfer, or gap junctions 3 . All cDC2 subsets and aDC2 efficiently induced CD4SP Treg differentiation, in agreement with reports from our lab and others that cDC2s more efficiently induce Tregs in vitro than cDC1s or pDCs 6,30,46 .…”

“…Though recent studies have documented roles for several DC subsets in thymocyte selection 3 , the relative ability of DC subsets to present TRAs on MHC-I and MHC-II and their capacity to induce Treg differentiation have not been comprehensively compared; furthermore, the cellular and molecular crosstalk signals that support homeostasis and/or activation of thymic DC subsets remain largely enigmatic. Here, we first identify the transcriptionally distinct subsets that comprise the thymic DC compartment through scRNA-seq at greater resolution than previously described 10,22,44 .…”

“…In addition to displaying self-peptides from their own proteome, DCs acquire and present diverse self-antigens to establish self-tolerance, including tissue-restricted antigens (TRAs) expressed by Aire + mTECs, circulating antigens, and peripherally-acquired antigens 3 .…”

“…Thymic DCs play a crucial role in central tolerance, as genetic ablation of DCs results in impaired negative selection and ensuing autoimmunity 2 . In addition to displaying self-peptides from their own proteome, DCs acquire and present diverse self-antigens to establish self-tolerance, including tissue-restricted antigens (TRAs) expressed by Aire + mTECs, circulating antigens, and peripherally-acquired antigens 3 .…”

Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs

“…Immune cells interact with Thymic Epithelial Cells (TECs) that are divided in cortical TECs (cTECs) and medullary TECs (mTECs), each type playing different functions and having different spatial distribution ( 44 ). The crosstalk between TECs and nascent thymocytes is crucial for T cell differentiation and maturation along with the establishment of “self-nonself discrimination” mechanisms aimed at the elimination of autoreactive T cells carrying self-reactive T cell antigen receptor (TCR) or diverting into thymic regulatory T cells ( 45 , 46 ).…”