Enteric Flora Expands Gut Lamina Propria CX3CR1+ Dendritic Cells Supporting Inflammatory Immune Responses under Normal and Inflammatory Conditions

Abstract

CD103 or CX3CR1 surface expression defines distinct dendritic cells (DCs) and macrophages in the murine lamina propria of the colon (cLP). We investigated the surface marker and functional phenotype of CD103+ and CX3CR1+ cLP DCs and their role in transfer colitis. cLP CD11c+ cells were isolated from specific pathogen-free or germ-free mice to elucidate the role of the commensal flora in their development. The cLP CD11c+ cells are a heterogeneous cell population that includes 16% CX3CR1+, 34% CD103+, 30% CD103−CX3CR1− DCs, and 17% CD68+/F4/80+CX3CR1+CD11c+ macrophages. All DCs expressed high levels of MHC II but low levels of costimulatory (CD40, CD86, and CD80) and coinhibitory (programmed death ligand-1) molecules. Ex vivo confocal microscopy demonstrated that CX3CR1+CD11c+ cells, but not CD103+ DCs, were reduced in the cLP of germ-free (CX3CR1-GFP) mice. The absence of the enteric flora prevents the formation of transepithelial processes by the CX3CR1+ DCs. CX3CR1+ DCs preferentially supported Th1/Th17 CD4 T cell differentiation. CD103+ DCs preferentially induced the differentiation of Foxp3-expressing regulatory T cells. The stimulation of cLP DCs with fractalkine/CX3CL1 increased the release of IL-6 and TNF-α. In the absence of CX3CR1, the CD45RBhigh CD4 transfer colitis was suppressed and associated with reduced numbers of DCs in the mesenteric lymph nodes and a reduction in serum IFN-γ and IL-17. The local bacteria-driven accumulation of CX3CR1+ DCs seems to support inflammatory immune responses.

Intestinal CX 3 C chemokine receptor 1 high (CX 3 CR1 high ) myeloid cells prevent T-cell-dependent colitis

“…CD103 + CX 3 CR1 − DCs have been shown to promote intestinal immune tolerance through the generation of Foxp3 + T reg cells (15,16,18,19). Intestinal macrophages are also reported to induce Foxp3 + T reg cells (22) a property to induce T reg cells (39,40).…”

“…These DCs have further been shown to induce development of Foxp3 + T reg cells (18)(19)(20). CX 3 CR1 + CD11b + DCs have been shown to mediate inflammatory responses through the induction of Th1 and Th17 cell development (15,(21)(22)(23)(24). In addition to these cell populations, CD103 + CX 3 CR1 − CD11b + cells and CD11b + CD11c − macrophages have been identified in the intestinal lamina propria (13,14,22,25).…”

“…In particular, CD103 + CX 3 CR1 − CD11b − dendritic cells (DCs) and CX 3 CR1 + CD11b + DCs have been well characterized (13)(14)(15). CD103 + CX 3 CR1 − CD11b − DCs have been shown to generate and activate gut-tropic CD8 + T cells (16,17).…”

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…52 In contrast, in experimental autoimmune encephalitis, both IL-17 and IFNg production and disease severity were enhanced in CX3CR1 2/2 mice compared with WT controls, however, this effect was not T cell intrinsic. 53 In colitis, IL-17A production was not affected or even increased in CX3CR1 2/2 mice, 54,55 which was attributed to defective intramural macrophage populations. 54 Regarding the other main TGFb-promoted T cell subgroup, T REG cells, these tended to 54 or were significantly reduced in CX3CR1 2/2 mice with colitis and T cell-mediated skin immunity.…”

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…The number of CX3CR1 + dendritic cells is reduced in germ free mice. This subset of dendritic cells preferentially supports Th1 and Th17 CD4 + T cell differentiation [35], in contrast to CD103 + DCs that preferentially induce differentiation of Foxp3 + regulatory T cells [36]. In general, the commensal bacteria in the gut have a significant impact on maturation of the gut immune system [37] and intestinal colonization contributes to combined effector and regulatory T cell responses.…”