Periodic Reporting for period 4 - TOLERANCE FOOTPRINT (Clonal Deletion versus Clonal Diversion: Footprints of Self-Tolerance in the T CellRepertoire)
Periodo di rendicontazione: 2022-04-01 al 2022-09-30
The antigen receptor repertoire is generated during immune cell development. In the case of T cells this happens in the thymus, where each developing cell is equipped with an individual antigen receptor (the T cell receptor; TCR) through random rearrangement of TCR gene segments. Importantly, owing to its random nature, this assembly of TCRs not only produces ‘useful’ T cells that potentially recognize invading microbes and viruses, but inevitably also leads to the emergence of potentially ‘dangerous’ T cells that carry autoreactive TCRs specific for the body’s own structures (so-called self-antigens).
A variety of mechanisms have been described that prevent autoreactive T cells from causing damage to tissues, collectively leading to a state of ‘self-tolerance’. A failure of self-tolerance can result in a variety of diseases such as type-1-diabetes or multiple sclerosis; collectively, these pathological conditions are referred to as autoimmune diseases. The precise aetiology of many autoimmune diseases is only insufficiently understood, and treatment regimens are mostly limited to general and unspecific immune suppression. Hence, there is a clear need for a deeper understanding of the physiological processes that maintain self-tolerance.
A classical concept of self-tolerance envisioned that autoreactive T cells would be eliminated early in their development, and this mechanism of clonal deletion has indeed been shown to purge a substantial fraction of autoreactive T cells from the T cell repertoire during thymic selection. More recently, it has become clear that there is a second, fundamentally different mechanism that operates through the ‘re-education’ of potentially dangerous autoreactive cells into harmless and beneficial regulatory T cells (Treg cells). Like clonal deletion, this process of cell-fate diversion into the Treg cells lineage can also be instructed during early T cell differentiation in the thymus, and the key parameters that distinguish between the two modalities of central T cell tolerance remain incompletely understood (Klein et al., 2019). The project ‘TOLERANCE FOOTPRINT’ has provided important insights into the determinants that specify whether an autoreactive CD4+ T cell is deleted or diverted into the Treg cell lineage and how both mechanisms together shape the composition of the T cell repertoire.
In a related line of investigation, we assessed the quantitative and qualitiative impact of T cell extrinsic determinants on shaping of the TCR repertoire (Aim 2). Here, we focused on thymic antigen presenting cells and their unique functional attributes. Commonly, dendritic cells and medullary thymic epithelial cells are believed to represent the key antigen presenting cells (APCs) for central T cell tolerance induction. We previously found that the thymus also harbours a distinct population of B cells that display unique properties: unlike their peripheral counterparts, thymic B cells express high levels of co-stimulatory molecules and MHC II. Moreover, they also express AIRE, a transcriptional co-activator that serves a crucial tolerogenic function in medullary thymic epithelial cells by promoting the expression of peripheral tissue-antigens (Yamano et al., 2015). Together, these potent APC features of thymic B cells suggested that they might serve a non-redundant role in central T cell tolerance induction. We established high throughput methodology for the generation and comparison of global inventories of TCR repertoires that are generated in the absence or presence of thymic B cells or under various circumstances in which thymic B cells were manipulated to lack the capacity to directly present antigens, to express autoantigens driven by AIRE, or to undergo B cell receptor class-switching, respectively. Together, these studies reveal that the tolerogenic ‘footprint’ of thymic B cells on the composition of the nascent TCR repertoire in the thymus is much larger than previously anticipated (or considered at all). These findings have not been published yet, but were presented and well received at a recent international conference on autoimmunity (Crete, 2022).