| 1. |
- Ahmadi, Fatemeh, et al.
(författare)
-
cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in mice
- 2023
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:3
-
Tidskriftsartikel (refereegranskat)abstract
- The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1-Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1-Th17 cell homeostasis.
|
|
| 2. |
- Annacker, O, et al.
(författare)
-
Essential role for CD103 in the T cell-mediated regulation of experimental colitis
- 2005
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 202:8, s. 1051-1061
-
Tidskriftsartikel (refereegranskat)abstract
- The integrin CD103 is highly expressed at mucosal sites, but its role in mucosal immune regulation remains poorly understood. We have analyzed the functional role of CD103 in intestinal immune regulation using the T cell transfer model of colitis. Our results show no mandatory role for CD103 expression on T cells for either the development or CD4(+)CD25(+) regulatory T (T reg) cell-mediated control of colitis. However, wild-type CD4(+)CD25(+) T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells in T reg cell-mediated intestinal immune regulation. Non-T cell expression of CD103 is restricted primarily to CD11c(high) MHC class IIhigh dendritic cells (DCs). This DC population is present at a high frequency in the gut-associated lymphoid tissue and appears to mediate a distinct functional role. Thus, CD103(+) DCs, but not their CD103(-) counterparts, promoted expression of the gut-homing receptor CCR9 on T cells. Conversely, CD103(-) DCs promoted the differentiation of IFN-gamma-producing T cells. Collectively, these data suggest that CD103(+) and CD103(+) DCs represent functionally distinct subsets and that CD103 expression on DCs influences the balance between effector and regulatory T cell activity in the intestine.
|
|
| 3. |
- Jaensson Gyllenbäck, Elin, et al.
(författare)
-
Small intestinal CD103(+) dendritic cells display unique functional properties that are conserved between mice and humans
- 2008
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:9, s. 2139-2149
-
Tidskriftsartikel (refereegranskat)abstract
- A functionally distinct subset of CD103(+) dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3(+) T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and alpha 4 beta 7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103(+) DCs. CD103(+) SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI- LP. BrdU pulse-chase experiments suggested that most CD103(+) DCs do not derive from a CD103(-) SI- LP DC intermediate. The majority of CD103(+) MLN DCs appear to represent a tissue- derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8(+) and CD4(+) T cells. In contrast, most CD103(+) MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103(+) DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103(+) MLN DCs isolated from SB Crohn ' s patients. Thus, small intestinal CD103(+) DCs represent a potential novel target for regulating human intestinal infl ammatory responses.
|
|
| 4. |
- Johansson Lindbom, Bengt, et al.
(författare)
-
Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing.
- 2005
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 202:8, s. 1063-1073
-
Tidskriftsartikel (refereegranskat)abstract
- Gut-associated lymphoid tissue (GALT) dendritic cells (DCs) display a unique ability to generate CCR9+α4β7+ gut-tropic CD8+ effector T cells. We demonstrate efficient induction of CCR9 and α4β7 on CD8+ T cells in mesenteric lymph nodes (MLNs) after oral but not intraperitoneal (i.p.) antigen administration indicating differential targeting of DCs via the oral route. In vitro, lamina propria (LP)–derived DCs were more potent than MLN or Peyer's patch DCs in their ability to generate CCR9+α4β7+ CD8+ T cells. The integrin α chain CD103 (αE) was expressed on almost all LP DCs, a subset of MLN DCs, but on few splenic DCs. CD103+ MLN DCs were reduced in number in CCR7−/− mice and, although CD8+ T cells proliferated in the MLNs of CCR7−/− mice after i.p. but not oral antigen administration, they failed to express CCR9 and had reduced levels of α4β7. Strikingly, although CD103+ and CD103− MLN DCs were equally potent at inducing CD8+ T cell proliferation and IFN-γ production, only CD103+ DCs were capable of generating gut-tropic CD8+ effector T cells in vitro. Collectively, these results demonstrate a unique function for LP-derived CD103+ MLN DCs in the generation of gut-tropic effector T cells.
|
|
| 5. |
- Johansson Lindbom, Bengt, et al.
(författare)
-
Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT): Requirement for GALT Dendritic Cells and Adjuvant.
- 2003
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:6, s. 963-969
-
Tidskriftsartikel (refereegranskat)abstract
- n the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin {alpha}4ß7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+{alpha}4ß7+CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut.
|
|
| 6. |
- Kunkel, E J, et al.
(författare)
-
Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity
- 2000
-
Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 192:5, s. 761-768
-
Tidskriftsartikel (refereegranskat)abstract
- The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.
|
|
| 7. |
- Schulz, Olga, et al.
(författare)
-
Intestinal CD103(+), but not CX3CR1(+), antigen sampling cells migrate in lymph and serve classical dendritic cell functions
- 2009
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 206:13, s. 3101-3114
-
Tidskriftsartikel (refereegranskat)abstract
- Chemokine receptor CX3CR1(+) dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103(+) DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103(+) DC, CX3CR1(+) cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103(+) DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1(+) cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103(+) DC. These findings indicate that selectively CD103(+) DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1(+) populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.
|
|
| 8. |
- Sitnicka Quinn, Ewa, et al.
(författare)
-
Complementary Signaling through flt3 and Interleukin-7 Receptor {alpha} Is Indispensable for Fetal and Adult B Cell Genesis.
- 2003
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:10, s. 1495-1506
-
Tidskriftsartikel (refereegranskat)abstract
- Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7R{alpha}, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7R{alpha} and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- x IL-7R{alpha}-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7R{alpha}-/- mice, FL-/- x IL-7R{alpha}-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7R{alpha} are indispensable for fetal and adult B cell development.
|
|
| 9. |
- Zabel, B A, et al.
(författare)
-
Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis
- 1999
-
Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 190:9, s. 1241-1256
-
Tidskriftsartikel (refereegranskat)abstract
- TECK (thymus-expressed chemokine), a recently described CC chemokine expressed in thymus and small intestine, was found to mediate chemotaxis of human G protein-coupled receptor GPR-9-6/L1.2 transfectants. This activity was blocked by anti-GPR-9-6 monoclonal antibody (mAb) 3C3. GPR-9-6 is expressed on a subset of memory alpha4beta7(high) intestinal trafficking CD4 and CD8 lymphocytes. In addition, all intestinal lamina propria and intraepithelial lymphocytes express GPR-9-6. In contrast, GPR-9-6 is not displayed on cutaneous lymphocyte antigen-positive (CLA(+)) memory CD4 and CD8 lymphocytes, which traffic to skin inflammatory sites, or on other systemic alpha4beta7(-)CLA(-) memory CD4/CD8 lymphocytes. The majority of thymocytes also express GPR-9-6, but natural killer cells, monocytes, eosinophils, basophils, and neutrophils are GPR-9-6 negative. Transcripts of GPR-9-6 and TECK are present in both small intestine and thymus. Importantly, the expression profile of GPR-9-6 correlates with migration to TECK of blood T lymphocytes and thymocytes. As migration of these cells is blocked by anti-GPR-9-6 mAb 3C3, we conclude that GPR-9-6 is the principal chemokine receptor for TECK. In agreement with the nomenclature rules for chemokine receptors, we propose the designation CCR-9 for GPR-9-6. The selective expression of TECK and GPR-9-6 in thymus and small intestine implies a dual role for GPR-9-6/CCR-9, both in T cell development and the mucosal immune response.
|
|
