Abstract
Interactions of developing T cells with Aire+ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEChi) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire+ mTEChi. However, it remains unknown whether thymocytes control the precursors of Aire+ mTEChi that are contained in mTEClo cells or other mTEClo subsets that have recently been delineated by single-cell transcriptomic analyses. Here, using three distinct transgenic mouse models, in which antigen presentation between mTECs and CD4+ thymocytes is perturbed, we show by high-throughput RNA-seq that self-reactive CD4+ thymocytes induce key transcriptional regulators in mTEClo and control the composition of mTEClo subsets, including Aire+ mTEChi precursors, post-Aire and tuft-like mTECs. Furthermore, these interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. This gene activation program induced in mTEClo is combined with a global increase of the active H3K4me3 histone mark. Finally, we demonstrate that these self-reactive interactions between CD4+ thymocytes and mTECs critically prevent multiorgan autoimmunity. Our genome-wide study thus reveals that self-reactive CD4+ thymocytes control multiple unsuspected facets from immature stages of mTECs, which determines their heterogeneity.
Highlights
The thymic medulla ensures the generation of a self-tolerant T-cell repertoire (Klein et al, 2014; Lopes et al, 2015)
The same results were observed with mTEClo purified from MHCII-/- mice, lacking CD4+ thymocytes, excluding any potential indirect effect of CIITA in the phenotype observed in ΔCD4 mice (Figure 1— figure supplement 3A)
Using three distinct transgenic models, we found that self-reactive CD4+ thymocytes control the developmental transcriptional programs from the mTEClo stage, including TAC-T ECs that precede Aire+ medullary thymic epithelial cells (mTECs)
Summary
The thymic medulla ensures the generation of a self-tolerant T-cell repertoire (Klein et al, 2014; Lopes et al, 2015). These bidirectional interactions between mTECs and thymocytes are commonly referred to as thymic crosstalk (Lopes et al, 2015; van Ewijk et al, 1994) It remains unknown whether CD4+ thymocytes act exclusively on mature Aire+ mTEChi or upstream on their TAC-T EC precursors contained in mTEClo and whether the development of the newly identified Fezf2+, post-A ire, and tuft-like subsets is regulated or not by CD4+ thymocytes. Our data reveal that self-reactive CD4+ thymocytes upregulate in mTEClo the expression of TRAs, chemokines, cytokines, and adhesion molecules involved in T-c ell development This gene activation program correlates with increased levels of the active trimethylation of lysine-4 of histone 3 (H3K4me3) mark, including the loci of Fezf2-dependent and Aire/Fezf2-independent TRAs, indicative of an epigenetic regulation for their expression. Our genome-wide study reveals that self-reactive CD4+ thymocytes control the developmental transcriptional programs of mTEClo, which conditions their differentiation and function as inducers of T-cell tolerance
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