Thymic iNKT single cell analyses unmask the common developmental program of mouse innate T cells

Abstract

Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of innate-like T cells differentiate into functionally distinct effector subsets during their development in the thymus. Here, we profiled >10,000 differentiating thymic invariant natural killer T (iNKT) cells using single-cell RNA sequencing to produce a comprehensive transcriptional landscape that highlights their maturation, function, and fate decisions at homeostasis. Our results reveal transcriptional profiles that are broadly shared between iNKT and mucosal-associated invariant T (MAIT) cells, illustrating a common core developmental program. We further unmask a mutual requirement for Hivep3, a zinc finger transcription factor and adapter protein. Hivep3 is expressed in early precursors and regulates the post-selection proliferative burst, differentiation and functions of iNKT cells. Altogether, our results highlight the common requirements for the development of innate-like T cells with a focus on how Hivep3 impacts the maturation of these lymphocytes.

Ontogenic timing, T cell receptor signal strength, and Notch signaling direct γδ T cell functional differentiation in vivo

“…Although cluster 10 had features of fully differentiated γδ NKT cells, the gene expression profile of cluster 1 was consistent with γδ NKT cell progenitors, and b/d++ contained significantly more cluster 1 cells compared with b/d+− ( Figure 6C ; Table S3 ). Of importance, cluster 1 had enriched expression of Hivep3 , which is shown to be expressed in NKT cell progenitors and required for the survival, differentiation, and function of NKT cells ( Harsha Krovi et al, 2020 ) ( Figure S9A ; Table S4 ). Other genes that defined cluster 1 and that may be involved in γδ NKT cell programming included Tnfrsf9 , Xcl1 , and Nrgn ( Figure S9A ; Table S4 ).…”

Multi-Dimensional Gene Regulation in Innate and Adaptive Lymphocytes: A View From Regulomes

“…The similarities between innate and adaptive lymphocyte programming have dramatically accelerated our understanding of ILC regulation using the knowledge accumulated from studies of T cells (11)(12)(13)(14). Other innate-like T cells, such as NKT cells, that mirror their functional T cell analogs also reveal similar lineage programming during development at both transcriptomic and epigenomic levels, which is beyond the scope of this review (15,16). Here, we will focus on how cell identity and function are epigenetically imprinted during ILC maturation and how environmental signals activate or maintain ILC regulomes that define their transcriptomes.…”

Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

“…Like conventional CD4 + T cells and ILCs, UT cells differentiate into discrete type 1 (IFN-γ-producing), type 2 (IL-4-producing) and type 3 (IL-17-producing) effector subsets ( Figure 1 ) that require the expression of the signature transcription factors T-bet, PLZF/GATA-3 and RORγt, respectively [ 36 , 44 , 45 ]. In mice, iNKT/MAIT/γδT1 and 17 can be found in various proportions in most tissues.…”

“…In mice, iNKT/MAIT/γδT1 and 17 can be found in various proportions in most tissues. Bona fide MAIT2 and γδT2 cells are virtually absent in mice [ 32 , 41 , 42 , 46 , 47 ], and the existence of a fully differentiated iNKT2 effector subset has recently been challenged [ 44 , 48 ]. UT cell effector subsets can differentiate in the thymus or in peripheral tissues [ 42 , 43 , 44 , 47 , 49 , 50 ].…”