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Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A - J. Exp. Med. (2012)

Bottom Line: The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan.Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations.Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

ABSTRACT
Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

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Pathogenic role of CAG in colitis of CD45RB model. CD4+CD45RBhigh naive T cells were purified from the spleen of WT (WT>RAG) versus T/C2GnT Tg (C2GnT>RAG) mice, and they were adoptively transferred i.v. into Rag1−/− mice. The recipients were sacrificed at 8 wk after transfer. (A) Representative colonic histologies (×10 objective) are shown. Colon of donor WT mouse is shown as normal control. Bars, 200 µm. (B) Disease scores evaluated by a combination of macroscopic and microscopic examinations are summarized. Each dot represents individual recipient. **, P < 0.0001. (C) Expression levels of IL-1β in the colonic tissues from WT mice and from Rag1−/− mice with transfer of WT-derived (WT>RAG) versus T/C2GnT tg–derived (C2GnT>RAG) CD4+ T cells are shown. n = 6/each group. *, P < 0.005.
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fig3: Pathogenic role of CAG in colitis of CD45RB model. CD4+CD45RBhigh naive T cells were purified from the spleen of WT (WT>RAG) versus T/C2GnT Tg (C2GnT>RAG) mice, and they were adoptively transferred i.v. into Rag1−/− mice. The recipients were sacrificed at 8 wk after transfer. (A) Representative colonic histologies (×10 objective) are shown. Colon of donor WT mouse is shown as normal control. Bars, 200 µm. (B) Disease scores evaluated by a combination of macroscopic and microscopic examinations are summarized. Each dot represents individual recipient. **, P < 0.0001. (C) Expression levels of IL-1β in the colonic tissues from WT mice and from Rag1−/− mice with transfer of WT-derived (WT>RAG) versus T/C2GnT tg–derived (C2GnT>RAG) CD4+ T cells are shown. n = 6/each group. *, P < 0.005.

Mentions: To examine whether the expression of CAG on CD4+ T cells plays any role in colitis, we examined a naive T cell–induced colitis model (CD45RB model; Izcue et al., 2009). In brief, CD4+CD45RBhigh naive T cells were purified from the spleen of WT versus T/C2GnT tg mice and transferred into Rag1−/− mice lacking T and B cells, and the recipient mice were sacrificed at 8 wk after cell transfer. As previously demonstrated (Izcue et al., 2009), the donor T cells from WT mice induced the development of severe colitis in the recipients (Fig. 3, A and B) and expressed the CAG in the inflamed colon (Fig. 2 E). In contrast, CD4+ T cells with restored expression of C2GnT were significantly less able to induce the development of colitis (Fig. 3, A and B), consistent with their inability to express the CAG (Fig. 2 E). As predicted, no colitis was found in control WT mice (Fig. 3 A). The disease severity was further supported by the colonic expression level of an inflammatory cytokine; significantly increased IL-1β expressions were observed in the colon of Rag1−/− mice reconstituted with WT-derived CD4+ T cells as compared with those reconstituted with T/C2GnT tg–derived CD4+ T cells (Fig. 3 C). These findings demonstrate that ability of CD4+ T cells to express CAG is a significant contributor to the exacerbation of this naive T cell–induced colitis.


Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A - J. Exp. Med. (2012)

Pathogenic role of CAG in colitis of CD45RB model. CD4+CD45RBhigh naive T cells were purified from the spleen of WT (WT>RAG) versus T/C2GnT Tg (C2GnT>RAG) mice, and they were adoptively transferred i.v. into Rag1−/− mice. The recipients were sacrificed at 8 wk after transfer. (A) Representative colonic histologies (×10 objective) are shown. Colon of donor WT mouse is shown as normal control. Bars, 200 µm. (B) Disease scores evaluated by a combination of macroscopic and microscopic examinations are summarized. Each dot represents individual recipient. **, P < 0.0001. (C) Expression levels of IL-1β in the colonic tissues from WT mice and from Rag1−/− mice with transfer of WT-derived (WT>RAG) versus T/C2GnT tg–derived (C2GnT>RAG) CD4+ T cells are shown. n = 6/each group. *, P < 0.005.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526363&req=5

fig3: Pathogenic role of CAG in colitis of CD45RB model. CD4+CD45RBhigh naive T cells were purified from the spleen of WT (WT>RAG) versus T/C2GnT Tg (C2GnT>RAG) mice, and they were adoptively transferred i.v. into Rag1−/− mice. The recipients were sacrificed at 8 wk after transfer. (A) Representative colonic histologies (×10 objective) are shown. Colon of donor WT mouse is shown as normal control. Bars, 200 µm. (B) Disease scores evaluated by a combination of macroscopic and microscopic examinations are summarized. Each dot represents individual recipient. **, P < 0.0001. (C) Expression levels of IL-1β in the colonic tissues from WT mice and from Rag1−/− mice with transfer of WT-derived (WT>RAG) versus T/C2GnT tg–derived (C2GnT>RAG) CD4+ T cells are shown. n = 6/each group. *, P < 0.005.
Mentions: To examine whether the expression of CAG on CD4+ T cells plays any role in colitis, we examined a naive T cell–induced colitis model (CD45RB model; Izcue et al., 2009). In brief, CD4+CD45RBhigh naive T cells were purified from the spleen of WT versus T/C2GnT tg mice and transferred into Rag1−/− mice lacking T and B cells, and the recipient mice were sacrificed at 8 wk after cell transfer. As previously demonstrated (Izcue et al., 2009), the donor T cells from WT mice induced the development of severe colitis in the recipients (Fig. 3, A and B) and expressed the CAG in the inflamed colon (Fig. 2 E). In contrast, CD4+ T cells with restored expression of C2GnT were significantly less able to induce the development of colitis (Fig. 3, A and B), consistent with their inability to express the CAG (Fig. 2 E). As predicted, no colitis was found in control WT mice (Fig. 3 A). The disease severity was further supported by the colonic expression level of an inflammatory cytokine; significantly increased IL-1β expressions were observed in the colon of Rag1−/− mice reconstituted with WT-derived CD4+ T cells as compared with those reconstituted with T/C2GnT tg–derived CD4+ T cells (Fig. 3 C). These findings demonstrate that ability of CD4+ T cells to express CAG is a significant contributor to the exacerbation of this naive T cell–induced colitis.

Bottom Line: The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan.Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations.Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

ABSTRACT
Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus