Defining the distinct functional roles of hematopoietic and stromal antigen presenting cells in the thymus

Abstract

The development of an effective but self-tolerant T cell repertoire is dependent thymic selection processes. Selection is mediated by thymic antigen presenting cells, as these APC present self-peptide:MHC complexes which bind T cell receptors on developing T cells. The APC subsets that provide the signals that determine thymocyte fate have varied localization and surface molecule expression, leading to distinct microenvironments throughout the thymus. Here, we sought to gain a better understanding of how thymic APC coordinate selection, particularly the selection of thymic IEL precursors and the production of type I interferon in the thymus. Using bone marrow chimeras, we found that hematopoietic APC are required for IELp selection. We then used various approaches to either selectively deplete MHCI on individual APC subsets or deplete the subset itself. However, no single thymic APC subset was required for IELp selection, and only broad defects MHCI expression on APC led to fewer Type A IELp, suggesting functional redundancy amongst these hematopoietic APC. Further, we also assessed the role of tonic type I interferon in the thymus by first determining its cellular source. We found that mTEChi produce IFN-I at the steady state, and this expression is AIRE-dependent. Further, using a reporter in which interferon-stimulated gene expression could be assessed, we found that most cells in the thymus respond to IFN-I and potentially other interferons as well. We then showed that this interferon signaling helps shape the thymic APC compartment, thereby likely influencing T cell selection. These findings provide valuable insight into how APC coordinate IELp selection and how these APC are influenced by other factors – like type I interferon – themselves.