Identification of a Lymphoid-Derived Plasmacytoid Dendritic Cell Subset with Distinct Functional Properties in Mice and Humans

Основные понятия

A novel subset of plasmacytoid dendritic cells (B-pDCs) is derived from common lymphoid progenitors and exhibits a unique gene expression profile and functional properties compared to classical myeloid-derived pDCs.

Аннотация

The content describes the identification of a novel mouse plasmacytoid dendritic cell (pDC) lineage that is derived from common lymphoid progenitors (CLPs) and is dependent on the expression of the transcription factor Bcl11a. These CLP-derived pDCs, referred to as "B-pDCs", have a distinct gene expression profile that includes hallmark B cell genes not normally expressed in conventional pDCs.
Functionally, B-pDCs exhibit reduced IFN-α secretion but enhanced T cell proliferation compared to canonical pDCs upon Toll-like receptor 9 (TLR9) engagement. Single-cell RNA sequencing analysis revealed that B-pDCs represent a phenotypically and transcriptionally distinct pDC subset that is specialized in T cell activation, in contrast to myeloid-derived pDCs.
The content also discusses the identification of another homogeneous subpopulation of myeloid-derived pDCs that express high levels of the cell-surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Overall, the results demonstrate the functional heterogeneity and developmental plasticity within the murine pDC compartment.

Статистика

Mb1-Cre deletion of Bcl11a results in a 25% reduction in pDC frequencies in the bone marrow.
Upon TLR9 activation, B-pDCs exhibit a 2-fold increase in cell numbers compared to classical pDCs.
B-pDCs produce significantly less IFN-α but more IL-12p40 than classical pDCs upon TLR9 stimulation.
B-pDCs are significantly more effective at expanding T cells in co-culture assays than classical pDCs.

Цитаты

"Relative to CD79a- pDCs, resting B-pDCs express higher levels of MHC Class II suggesting that they may be primed for immediate response to pro-inflammatory signals."
"IFN-α production was almost negligible in B-pDC, yet IL-12p40 production was significantly augmented over pDC."
"Altogether, our results showed B-pDCs were significantly better at expanding T cells in co-cultures than conventional pDCs upon TLR9 activation."

Ключевые выводы из

Lymphoid origin of intrinsically activated plasmacytoid dendritic cells in mice

by Dekker,J. D.... в www.biorxiv.org 04-28-2018

https://www.biorxiv.org/content/10.1101/310680v6

Дополнительные вопросы

What are the potential implications of the functional differences between B-pDCs and classical pDCs in the context of immune responses and disease pathogenesis

The functional differences between B-pDCs and classical pDCs have significant implications for immune responses and disease pathogenesis. B-pDCs, derived from common lymphoid progenitors (CLPs), exhibit a unique gene expression profile that includes hallmark B cell genes not typically expressed in conventional pDCs. Despite expressing classical pDC markers, B-pDCs lack IFN-α secretion and display a distinct inflammatory profile. This suggests that B-pDCs may play a role in promoting tolerogenic immune responses rather than the typical antiviral immune responses associated with classical pDCs. In the context of autoimmune diseases characterized by a type I IFN signature, the presence of B-pDCs could potentially modulate the immune response and contribute to disease pathogenesis. Additionally, the enhanced ability of B-pDCs to induce T cell proliferation following TLR9 engagement suggests a specialized role in T cell activation, which could impact adaptive immune responses in various disease states.

How might the developmental origins of B-pDCs versus myeloid-derived pDCs influence their distinct functional properties

The developmental origins of B-pDCs versus myeloid-derived pDCs play a crucial role in shaping their distinct functional properties. B-pDCs, arising from CLPs post T-B bifurcation, retain expression of early B cell receptor genes while also expressing pDC-associated genes. This unique transcriptional profile suggests that B-pDCs have a bipotential lineage capacity, diverging from B cell commitment after Ly6d expression. On the other hand, myeloid-derived classical pDCs originate from myeloid progenitors and exhibit a different gene expression pattern. The distinct developmental pathways of these pDC subsets likely contribute to their functional differences, with B-pDCs specializing in inflammatory responses, antigen presentation, and T cell activation. Understanding the developmental origins of pDC subsets provides insights into their unique functions and potential roles in immune regulation and disease pathogenesis.

Could the identification of these pDC subsets with divergent transcriptional and functional profiles lead to the development of more targeted therapeutic approaches for diseases involving pDCs

The identification of pDC subsets with divergent transcriptional and functional profiles opens up new possibilities for more targeted therapeutic approaches in diseases involving pDCs. By specifically targeting B-pDCs or classical pDCs based on their distinct properties, researchers and clinicians can develop tailored interventions to modulate immune responses in a more precise manner. For example, in autoimmune diseases characterized by a type I IFN signature, therapies that selectively target B-pDCs to promote tolerogenic immune responses while dampening inflammatory reactions mediated by classical pDCs could be explored. Additionally, the enhanced T cell activation capacity of B-pDCs suggests a potential role in enhancing immune responses in certain contexts. By understanding the unique characteristics of pDC subsets, novel therapeutic strategies can be developed to manipulate immune responses and potentially treat a range of diseases more effectively.