A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner

Abstract

During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here we show that the first wave of thymic progenitors comprises a unique population of bipotent cells generating lymphoid tissue inducer, in addition to invariant Vg5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and more precisely the lymphoid tissue inducer associated transcripts were expressed in the first but not in the second wave of thymic progenitors. Depletion of early thymic progenitors in a temporally-controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator expressing medullary thymic epithelial cells. We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid associated transcripts in yolk sac erythro-myeloid restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.

Hematopoiesis: A Layered Organization Across Chordate Species

“…Vγ5 + T cells and LTi cells, a subset of group 3 innate lymphoid cells (ILC3), are required to establish a mature compartment (Aireexpressing) of mTEC (Roberts et al, 2012). In line with this work, Elsaid et al (2020) showed that the first wave of TSP generates invariant γδ T cells and LTi within a thymic microenvironment and that temporal depletion of this wave resulted in loss of (Aire)expressing mTEC at birth (Figure 4). The crosstalk between the progeny of the first TSP and immature mTEC ensures that mature Aire + mTEC are in time and place to induce tolerance (see Table 1) in the nascent αβ T cell repertoire during the neonatal period.…”

“…Corroborating these observations, single-cell transcriptional and epigenetic analysis of IAHC detected a population of lymphomyeloid-primed progenitors, suggesting an early differentiation process or an HSC-independent generation (Zhu et al, 2020). Alternatively, or complementarily, despite a transient expression of lymphoid transcripts, the reported YS-derived LMP were devoid of lymphoid potential and therefore do not qualify as lymphoid progenitors (Elsaid et al, 2020).…”

“…The first thymic seeding progenitors (TSP) that colonize the embryonic thymus display a unique capacity to generate innate and innate-like lymphocytes. These cells are required to shape the thymic architecture, thus ensuring life-long efficient T cell tolerance and avoiding autoimmunity (Elsaid et al, 2020).…”

“…These progenitors differentiate rapidly, exhibit low proliferative capacity, express transcripts related to the ILC lineage, and are the only ones with the capacity to generate Vγ5 + T cells and LTi cells. A second wave of more immature hematopoietic progenitors colonize the thymus after E15 and ensure thymopoiesis thereafter (Figure 5; Ramond et al, 2014;Elsaid et al, 2020).…”

“…Due to their stage-restricted development, it is tempting to hypothesize that these particular lymphoid subsets originate from specialized cells that develop independent from HSC. The demonstration that B1 and B2 cells share a similar cellular origin (Kristiansen et al, 2016), that Vγ5-expressing T cells do not differentiate from conventional YS progenitors, and that embryonic hematopoietic progenitors often express lymphoid specific transcripts, regardless of their differentiation potential, offer alternative possibilities that need to be further investigated (Elsaid et al, 2020).…”