Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity

Abstract

Highlights d cDC2 initiate activation but not differentiation of antitumor CD4 + T conv d T reg depletion relieves cDC2 suppression driving antitumor CD4 + T conv differentiation d Human equivalent of mouse cDC2 are present in the tumor and draining lymph node d The balance of human cDC2/T reg in the TME dictates T cell quality and prognosis

ACKR4 restrains antitumor immunity by regulating CCL21

“…3 F), suggesting that the increased abundance of cDC2s in tumors in Ackr4 −/− hosts is not related to a defect in migration from tumor to LN. This difference in migration may reflect altered control of cDC2 egress compared with that of CD103 + DCs, a precedent being the recent observation that regulatory T cells can specifically hinder egress of cDC2, but not CD103 + DC from tumors (Binnewies et al, 2019), although these data do not rule out a role for increased recruitment of DCs into the tumor. Regardless, these data support a model whereby ACKR4 regulates migration of CD103 + DCs within the tumor microenvironment.…”

DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

“…In the mouse, Clec9a expression is highly restricted to type 1 conventional DCs (cDC1s) (10)(11)(12)(13), common DC progenitors (CDP), and pre-DC progenitors (14), and it is also expressed at low levels in plasmacytoid DCs (pDCs) (10,13,14). DNGR-1 is, however, not expressed by human pDCs and is highly restricted to human cDC1s in blood (11,15,16), lymphoid organs (16,17), and peripheral tissues (16), including tumors (18,19). Of note, in a mouse model that allows genetic tracing using a fluorescent protein that is stably expressed upon DNGR-1 expression (Clec9a-Cre), almost exclusively DCs are labeled, with some signal also among populations traditionally thought to represent red pulp macrophages and lung and kidney CD64 + cells that might derive from DC precursors (14,20).…”

Dendritic cells require TMEM176A/B ion channels for optimal MHC II antigen presentation to naive CD4+ T cells

“…We initially reported that Tmem176a/b were highly expressed in cDCs but not in pDCs 10,17 , likely a consequence of E2-2-mediated repression as revealed by Ghosh et al for Tmem176a 48 . Remarkably, recent mouse and human single-cell RNA-seq analysis highlighted these homologs as markers of selective DC subsets, both in mouse and human [49][50][51] . Notably, the association of TMEM176B expression with a subset of cDC2 in Binnewies et al 51 is concordant with our data in the mouse showing that Tmem176a/b are markedly over-expressed in cDC2 compared to cDC1.…”

“…Remarkably, recent mouse and human single-cell RNA-seq analysis highlighted these homologs as markers of selective DC subsets, both in mouse and human [49][50][51] . Notably, the association of TMEM176B expression with a subset of cDC2 in Binnewies et al 51 is concordant with our data in the mouse showing that Tmem176a/b are markedly over-expressed in cDC2 compared to cDC1. cDC2 exhibit an overall dominance in MHC II presentation in vivo resulting from the combination of their intrinsic efficiency 28,52 and their favorable position within lymphoid tissues for antigen uptake 53 .…”