Chicago - 12:00 PM - 1:00 PM
Microbiology-Immunology Seminar Series
Abstract: Subsets of classical dendritic cells (cDCs) have been defined on the basis of both surface marker patterns and by transcription factor dependence. Evidence of lineage level diversification among dDCs has been limited to two main branches, cDC1 and cDC2, distinguished by either high or low IRF8 expression, respectively, with the latter having some functional dependence on IRF4. These two cDC lineages may contain further functional and genetic heterogeneity, with transcriptional programs meditated by KLF4 (cDC2b) or Notch2 (cDC2a) signaling appearing to distinguish cDC2 subsets required selectively for promoting type 2 or type 3 immune responses. All these cDCs develop from a common dendritic cell progenitor (CDP) that also gives rise to a related but distinct lineage of plasmacytoid DCs. Research efforts are currently directed at two major issues; what are the genetic molecular events governing the diversification of the CDP; and what are the functional effector mechanisms that govern the specialized cellular activities of cDC1, cDC2a and cDC2b that allow these subsets to manifest distinct non-redundant activities in various types of infections. Specifically, although specified and committed progenitors for cDC1 and cDC2 have been identified, only the transcription factor Batf3 has been ascribed with a specific activity in the process of commitment, acting to stabilize IRF8 expression at a defined enhancer, with specification of cDC1, and the pathways in DC2s, still being obscure. The interactions and epistasis between the known relevant transcription factors, E2A, Id2, Nfil3, Zeb2, E2.2, IRF8 and IRF4, and others, are still a matter of study. Moreover, the pathway of progenitor diversification identifies at least two populations of cells committed to the cDC2 branch, but whether these each give rise to distinct or to overlapping functional mature cDC2 cells is unclear. On the functional front, while some progress into the unique cross-presentation (XP) capacity of cDC1 cells has been made by the identification of Rab43 as cDC1-specific protein promoting XP, it is not the whole basis for this XP capacity in these cells, leaving several other uniquely cDC1 genes in need of examination, including XCR1, Gcet2, Snx22, Itga8, and others. Further, the unique requirement for these cells as a critic source of IL-12 in certain infections has not been explained at a molecular level, with neither innate sensing nor cytokine response being identified as an unambiguous distinction. Further, although cDC2a cells are known to be a uniquely critical source of IL-23 in defense against some pathogens, the molecular basis for this is again poorly understood. Finally, the cDC2b program dependent on KLF4 for inducing or maintaining Th2 responses to Schistosomaisis mansoni is not understood at even a cellular, highlighting an urgent need for continued study. A variety of these issues will be discussed as time allows.
Kenneth Murphy, MD, PhD
First Centennial Professor of Pathology & Immunology
Investigator, Howard Hughes Medical Institute
Host: Dr. Chyung-Ru Wang