Abstract
In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-β in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.
Highlights
In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly selfreactive cells
The production of RANKL, which acts in synergy with CD40L to induce AIRE expression in mTEC7,11, was three to four times selectively decreased in highly autoreactive thymocytes, a population we previously reported to be the key thymocytes providing signals for medullary thymic epithelial cells (mTECs) differentiation[7] (Fig. 4a, b)
Our findings demonstrate that negative selection, both in the cortex and in the medulla, is dependent on TGF-β signaling in thymocytes, revealing an unsuspected role of this cytokine in this pivotal event for central tolerance (Fig. 7)
Summary
The T lymphocyte repertoire is purged of a substantial portion of highly selfreactive cells. Cortical thymocytes that passed the first wave of negative selection pursue their maturation program from the DP to the single-positive (SP) stage, where they acquire CCR7 expression allowing their migration from the cortex to the medulla, which is enriched in CCR7 ligands, CCL19 and CCL213–6 There, their physical interaction with medullary thymic epithelial cells (mTECs) leads to mTEC differentiation[7,8]. Mature mTECs have a unique ability to express and present a wide range of tissuerestricted antigens (TRAs) representing almost all peripheral tissue self-antigens on their MHC9 This promiscuous gene expression program is regulated, at least in part, by the transcriptional regulator AIRE (AutoImmune REgulator) and largely contributes to the medullary negative selection of highly autoreactive SP thymocytes[10]. In both cortical and medullary negative selection, the elimination of highly autoreactive thymocytes is mainly mediated by the pro-apoptotic BH3-only protein (BIM) in response to the strength of signals induced by the TCR-self-peptide-MHC interaction[12]
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