A New Subset of CD103+CD8α+ Dendritic Cells in the Small Intestine Expresses TLR3, TLR7, and TLR9 and Induces Th1 Response and CTL Activity

Abstract

CD103+ dendritic cells (DCs) are the major conventional DC population in the intestinal lamina propria (LP). Our previous report showed that a small number of cells in the LP could be classified into four subsets based on the difference in CD11c/CD11b expression patterns: CD11chiCD11blo DCs, CD11chiCD11bhi DCs, CD11cintCD11bint macrophages, and CD11cintCD11bhi eosinophils. The CD11chiCD11bhi DCs, which are CD103+, specifically express TLR5 and induce the differentiation of naive B cells into IgA+ plasma cells. These DCs also mediate the differentiation of Ag-specific Th17 and Th1 cells in response to flagellin. We found that small intestine CD103+ DCs of the LP (LPDCs) could be divided into a small subset of CD8α+ cells and a larger subset of CD8α− cells. Flow cytometry analysis revealed that CD103+CD8α+ and CD103+CD8α− LPDCs were equivalent to CD11chiCD11blo and CD11chiCD11bhi subsets, respectively. We analyzed a novel subset of CD8α+ LPDCs to elucidate their immunological function. CD103+CD8α+ LPDCs expressed TLR3, TLR7, and TLR9 and produced IL-6 and IL-12p40, but not TNF-α, IL-10, or IL-23, following TLR ligand stimulation. CD103+CD8α+ LPDCs did not express the gene encoding retinoic acid-converting enzyme Raldh2 and were not involved in T cell-independent IgA synthesis or Foxp3+ regulatory T cell induction. Furthermore, CD103+CD8α+ LPDCs induced Ag-specific IgG in serum, a Th1 response, and CTL activity in vivo. Accordingly, CD103+CD8α+ LPDCs exhibit a different function from CD103+CD8α− LPDCs in active immunity. This is the first analysis, to our knowledge, of CD8α+ DCs in the LP of the small intestine.

Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

“…Additionally, the B subunit of heat-labile enterotoxin can induce cells with a regulatory phenotype after intranasal administration (40), although it is not clear if these are primed by CD103 + DCs. The increased TLR5 expression in LP DCs over splenic DCs (18,19) (41). Despite the LP DC having the highest levels of TLR5 expression, T cell responses to flagellin can initiate in the spleen (21,28,34), without additional increases in DC numbers.…”

Immunity to gastrointestinal nematode infections

“…121 Similarly, the MAP3 (mitogen-activated protein kinase kinase kinase) kinase TPL-2 was also shown to modulate immunity to H. polygyrus, as its deletion in dendritic cells resulted in enhanced resistance to infection that was attributed to its downstream influence on the homing of leukocytes. 122 Indeed, different dendritic cell subsets have divergent expression of certain cytokine and pattern-recognition receptors, [123][124][125][126] and might thus be inherently more or less prone to respond to specific pathogens and cytokines to begin with. These types of signals, in combination with cell-extrinsic cues from epithelial and innate immune cells, could determine which type of dendritic cell that gets activated upon parasite infection.…”

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

“…Quantitative real-time PCR was carried out with primers, purchased from Applied Biosystems, specific for IL-6, TNF, IFN-b, and 18S rRNA, as an internal control, using a 7700 Sequence Detector (Applied Biosystems) as described previously (31). RT-PCR analysis was conducted on cDNA samples with the following primers: human AZI2 (forward: 59-ggatgcactggtagaagatgatatctg-39, reverse: 59-tcagctggaggagttctacttctttagat-39) and GAPDH (forward: 59-cttactccttggaggccatg-39, reverse: 59-ttagcccccctggccaagg-39).…”