A Discrete Subpopulation of Dendritic Cells Transports Apoptotic Intestinal Epithelial Cells to T Cell Areas of Mesenteric Lymph Nodes

Abstract

This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class IIhi, and express OX62, CD11c, and B7. CD4+/OX41+ DCs are strong antigen-presenting cells (APCs). CD4−/OX41− DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell–restricted cytokeratins, and nonspecific esterase (NSE)+ inclusions, not seen in OX41+ DCs. Identical patterns of NSE electrophoretic variants exist in CD4−/OX41− DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE+ DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE+ DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

“…This is also true for afferent lymph DC in other species [11][12][13]. Importantly, we have also shown that this phenotypic heterogeneity correlates with different functions in vivo, as iL-DC expressing low levels of CD172a selectively carry apoptotic material derived from intestinal epithelial cells to the T cell areas of the mesenteric lymph nodes (MLN) [2].…”

“…The subset-specific lack of TLR7/8 expres-sion could be important for tolerance to self antigens, as the CD172a low iL-DC lacking TLR7 and 8 expression will be less likely to respond to their cargo of cellular debris, which includes ssRNA. That this could be important for self tolerance is supported by murine studies showing that CD8a + DC, which share the selective ability to take up dying cells in vivo [2,3], do not express TLR7, whereas CD8a -DC do [16].…”

“…We have previously shown that CD172a low iL-DC selectively transport apoptotic intestinal epithelial cells to T cell areas of MLN [2]. ssRNA, both viral and self ( [29,30] and C. Reis e Sousa, personal communication), is the natural ligand for TLR7 or 8, depending on the species.…”

“…Importantly, this phenotypic heterogeneity correlates directly with functional specialization, e.g. uptake of dying cells, secretion of cytokines and skewing of T helper cell differentiation [2][3][4][5]. DC migrating via afferent lymph from peripheral tissues to draining LN both activate naive CD4 + T cells and transduce information that determines the differentiation of the activated cells.…”

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

“…Tolerance Introduction DC are professional antigen-presenting cells, which are well positioned in peripheral tissues to capture foreign antigens. DC are phagocytic and can ingest apoptotic cells, and hence are affected by the death of other cells in close proximity [1][2][3]. Clearance of apoptotic cells results in their removal from tissues, and provides protection from release of pro-inflammatory contents.…”