Abstract
SummaryDendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
Highlights
The vast array of infectious and non-infectious challenges faced by the vertebrates ranging from bacteria and viruses to parasites, toxins, and noxious substances requires distinct immune defense strategies reflected in diversification among effector cells of the adaptive immune system, foremost, CD4 T cells
Unbiased Dissection of Dendritic cells (DCs) Subsets by Single-Cell RNA-Seq The transcription factor T-bet delineates subsets of innate lymphoid cells (ILCs) and T helper cells with distinct effector programs, and its expression has been reported in DCs (LugoVillarino et al, 2003)
History of T-bet expression marked by YFP was not detectable in cDC1s indicating that T-bet expression is acquired after DC progenitors commit to cDC2 cell fate
Summary
The vast array of infectious and non-infectious challenges faced by the vertebrates ranging from bacteria and viruses to parasites, toxins, and noxious substances requires distinct immune defense strategies reflected in diversification among effector cells of the adaptive immune system, foremost, CD4 T cells. Classical DCs (cDCs), defined by the expression of integrin-aX (CD11c) and major histocompatibility complex class II (MHC class II) (Steinman et al, 1979), comprise two subsets, cDC1s and cDC2s (Guilliams et al, 2014) This initial division reflects developmental and functional heterogeneity among DCs. cDC1s, identified by cell surface expression of XCR1, CD8a, CLEC9A, or CD103 (Durai and Murphy, 2016), are developmentally dependent on IRF8 and BATF3 (Aliberti et al, 2003; Hildner et al, 2008). Our understanding of cDC2 heterogeneity and its biological implications has been limited by a lack of knowledge of its transcriptional basis, required for the development of genetic tools to selectively target DC subsets
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