Intestinal CD103− dendritic cells migrate in lymph and prime effector T cells

Abstract

Intestinal dendritic cells (DCs) continuously migrate through lymphatics to mesenteric lymph nodes where they initiate immunity or tolerance. Recent research has focused on populations of intestinal DCs expressing CD103. Here we demonstrate, for the first time, the presence of two distinct CD103(-) DC subsets in intestinal lymph. Similar to CD103(+) DCs, these intestine-derived CD103(-) DCs are responsive to Flt3 and they efficiently prime and confer a gut-homing phenotype to naive T cells. However, uniquely among intestinal DCs, CD103(-) CD11b(+) CX(3)CR1(int) lymph DCs induce the differentiation of both interferon-γ and interleukin-17-producing effector T cells, even in the absence of overt stimulation. Priming by CD103(-) CD11b(+) DCs represents a novel mechanism for the rapid generation of effector T-cell responses in the gut. Therefore, these cells may prove to be valuable targets for the treatment of intestinal inflammation or in the development of effective oral vaccines.

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

“…In agreement with a critical role for CCR7 in this process (9,13,39), we show that the accumulation of BrdU-labeled CD103 + DCs in the MLN is essentially shut off in CCR7 2/2 mice. Further to this, our BrdU pulse-chase experiments show that MHC-II high DCs accumulate with a delayed kinetics in the MLN as compared with their MHC-II low counterparts, which is consistent with the MHC-II high phenotype of all DCs in mesenteric lymph (15,40). This result therefore confirms that relative expression levels of MHC-II can be used as a criterion for discriminating between migratory and resident DCs in the MLN.…”

“…The large majority of MLN CD103 + DCs appears to represent small intestinal (SI) lamina propria (LP)-derived migratory DCs as they are selectively reduced in MLN, but not in the SI LP, of CCR7-deficient mice (9,13) and in BrdU pulse-chase experiments accumulate with delayed kinetics in the MLN compared with the SI LP (14). Consistent with this, the majority of DCs in thoracic duct lymph collected from mice after mesenteric lymphadenectomy express CD103 (15). However, a small proportion of DCs in such preparations lacks CD103 expression, for which reason CD103 appears less suitable to serve as a retrospective marker for all SI LP-derived DCs in the MLN (15).…”

“…Whereas only a minor proportion of the MHC-II low MLN DCs expressed CD103 (14 6 3%, n = 24), the frequencies of CD103 + CD11b + , CD103 + CD11b 2 , and CD103 2 (coexpressing CD11b or not) DCs within the MHC-II high gate appeared to mirror the previously described composition of intestinal lymph DCs (15) (Fig. 1A, 1B).…”

“…Because the induction of oral tolerance to fed soluble Ags requires migration of APCs from the SI LP to the draining MLN (13), (15,30), we have in this study addressed the mechanism by which SI LP CD103 + DCs are recruited to the MLN in the steady state. Our results reveal that deficiency in the TLR signaling adapter molecule MyD88 is associated with a 50-60% reduction in CD103 + DC migration, affecting both the CD103 + CD11b + and CD103 + CD11b 2 DC subsets, and that MyD88-signaling in CD11c + cells accounts for this effect.…”

“…However, a small proportion of DCs in such preparations lacks CD103 expression, for which reason CD103 appears less suitable to serve as a retrospective marker for all SI LP-derived DCs in the MLN (15). As DCs with high-level expression of MHC class II (MHC-II) are selectively absent from skin-draining LN in CCR7-deficient mice (8), and mesenteric lymph-borne DCs uniformly display a MHC-II high phenotype (15), migratory and LN-resident DCs in the MLN under steady state are currently more often distinguished based on relative levels of MHC-II expression.…”