functionally-specialized dendritic cells with distinct requirements for MyD88 2
Jie Liang1, Hsin-I Huang1, Fernanda P. Benzatti, Amelia B. Karlsson1,3, Junyi J. Zhang1 , Laura P. Hale , and Gianna E. Hammer1,* 1
Department of Immunology, 2Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
Interactions among Microbiota, DCs and T cells during IBD pathogenesis mune cells, including mucosal T cells. While microbiota-reactive T cells naturally occur during healthy conditions, an increase in abundance, stimulation, or function of these T cells is thought to contribute to the development and mainte-
Dendritic cells (DCs) are specialized antigen presenting cells (APCs) that sense microbes, activate naïve T cells, and regulate immune responses. Τhree + CD11b– DCs, CD103+CD11b+ DCs and CD103–CD11b+ DCs. Normal dynamics between microbiota, DCs, and T cells support modest numbers of IFNγ-producing, T helper 1 (Th1) and IL-17-producing (Th17) mucosal CD4 T cells, although these T cells The conditions under which Th1 and Th17
Results
Results
MyD88-independent pathways in DC cause expansion of Th1 and Th17 cells in DCA20-/- mice.
APC functions of intestinal DCs require CD80/86 to instruct IFNγ+ T cells and IL-6 to instruct IL-17 + T cells
DCs from A20cko
A20wt
trol antibody (iso)
Cell number of SI-LP CD4+ T cells, IFNγ+, IL-17+, IFNγ+IL-17+ and Foxp3+CD4+ T cells from mice of the indicated genotype.
expansion of pathological mucosal T cells
cause IBD, remain poorly understood.
Does Myd88-dependent or -independent pathway trigger IBD? We have found that A20
CD11c-cre mice (DCA20-/-) developed spontaneous
Numbers of IFNγ+ or IL-17+ T cells in DC-T cell co-cultures of the indicated DC subset, from A20wt or A20cko mice. Blocking antibodies to CD80/86 (A-D), IL-6 (E-H), or isotype control antibody (iso) were included in each co-culture.
MyD88-independent. We tested the role of MyD88-independent signaling pathways in DC function and IBD pathogenesis by generating mice whose DCs lack both A20 and MyD88 (DCA20-/-MyD88-/- mice).
+
+
–
+
CD103 CD11b DCs and CD103 CD11b DCs are required to ex
Results DCA20-/intestine, in a MyD88-independent fashion
(A) (C) Proximal small intestine is shown from co-housed mice of indicated genotype at 16 weeks of age. S = stomach; white bar indicates small intestine. (B) (D) Organ weights of small intestine from mice of the indicated genotype.
Mice were treated with antibiotics for 10 weeks. Bacterial 16S rDNA in stool (A) SI organ weight (b) and SI-LP Th17 (c) Th1 (d) and IFNg+IL-17+ CD4 T cells (e).
Each SI-LP DC subset possesses unique APC functions, and differential requirements for MyD88 signals
cko -DTA– mice and A20cko-DTA+ mice at 9-12 weeks of age. (B) Relative number of each SI-LP DC subset, (C) Total number of Th17, Th1, IL-17+IFNγ+ and Foxp3+ CD4 T cells were shown.
MyD88-independent pathways trigger spontaneous DC maturation in DCA20-/- mice
Conclusion
(A) Pathologic score of the indicated region of small intestine. Representative histology of terminal ileum is shown. Granulomas and crypt abcesses were frequently observed. Cell surface expression of maturation markers CD80 (B), CD86 (C) CD40 D) and total cell number (E) of SILP DCs and macrophages (Mac). Cellular expression of maturation markers is represented as cence intensity (MFI) relative to that of the same population in wildtype (A20wt) mice.
cko mice) and that the signals perceived, cellular responses, and antigen presenting cell (APC) functions are unique for each DC subset. Thus, while CD103+CD11b– DCs exclusively upregulate IFNγ-inducing APC functions, upregulated functions of CD103+CD11b+ DCs exclusively induce IL-17+ T cells. APC functions of CD103+CD11b– DCs require CD80/86 and CD103+CD11b+ DCs require IL-6 and, surprisingly, functions of both of these DCs are upregulated in a MyD88-independent fashion. In contrast, CD103–CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells, and of these two, only the IL-17-inducing APC functions require
(Α-C)(E) Three subsets of SI-LP DCs were isolated from mice of the indicated genotype and in+ and IL-17+ T cells, the percentages of IFNγ+ or IL-17+ and IL-17 protein in each DC-T cell coculture were shown. (D) The percentages of IL-17+IFNγ + from co-cultures above. (E) DC-T cell co-cultures of CD103-CD11b+ DCs from MyD88cko (A20-wt) mice.
A20cko mice. We further show that CD103–CD11b+ DCs and CD103+CD11b+ DCs are required to ex-
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