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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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CAG. (A) Galectin-4 (Gal4) binding patterns on lamina propria cells (including CD4+ versus CD4− cells) in normal colon of WT mice and inflamed colon of CD45RB model are shown. Data shown are one representation of seven independent experiments. (B) Intensities of galectin-4 binding on CD4+ T cells from the colon, lung, and liver of WT mouse, CD45RB model, and concanavalin A–induced hepatitis model (right panel) are shown. The results are representative in 3–12 mice in each group. (C) Intensities of galectin-3 (Gal3) and galectin-8 (Gal8) binding on CD4+ T cells from the colon of WT mouse and from the inflamed colon of CD45RB model are shown. The results are representative in 3 mice in each group. (D) Colonic tissues from healthy individuals (n = 5) and from patients with UC (n = 6), CD (n = 4), or Campylobacter infection (n = 2) were co-stained with FITC–anti-CD4 (green, left) and Alexa Fluor 594–labeled recombinant human galectin-4 (red, middle). Overlap images are shown on the right. Bars, 25 µm. (E) Flow cytometric analysis shows the intensity of galectin-4 binding on CD4+ (top) or CD8+ (bottom) T cells from inflamed colon (active, n = 10), noninvolved colon (inactive, n = 5), and peripheral blood (PBMC, n = 2) of UC patients and from normal colon of control subjects (normal, n = 4).
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fig1: CAG. (A) Galectin-4 (Gal4) binding patterns on lamina propria cells (including CD4+ versus CD4− cells) in normal colon of WT mice and inflamed colon of CD45RB model are shown. Data shown are one representation of seven independent experiments. (B) Intensities of galectin-4 binding on CD4+ T cells from the colon, lung, and liver of WT mouse, CD45RB model, and concanavalin A–induced hepatitis model (right panel) are shown. The results are representative in 3–12 mice in each group. (C) Intensities of galectin-3 (Gal3) and galectin-8 (Gal8) binding on CD4+ T cells from the colon of WT mouse and from the inflamed colon of CD45RB model are shown. The results are representative in 3 mice in each group. (D) Colonic tissues from healthy individuals (n = 5) and from patients with UC (n = 6), CD (n = 4), or Campylobacter infection (n = 2) were co-stained with FITC–anti-CD4 (green, left) and Alexa Fluor 594–labeled recombinant human galectin-4 (red, middle). Overlap images are shown on the right. Bars, 25 µm. (E) Flow cytometric analysis shows the intensity of galectin-4 binding on CD4+ (top) or CD8+ (bottom) T cells from inflamed colon (active, n = 10), noninvolved colon (inactive, n = 5), and peripheral blood (PBMC, n = 2) of UC patients and from normal colon of control subjects (normal, n = 4).

Mentions: An endogenous glycan-binding protein family, the galectins, is composed of 15 members that recognize different carbohydrate epitopes and play different roles (e.g., anti- versus proinflammatory) in immune responses (Lowe, 2001; Baum and Crocker, 2009; Hsu et al., 2009; Rabinovich and Toscano, 2009). We previously demonstrated that an increased binding of galectin-4 is specifically seen on CD4+ T cells in the inflamed, but not normal, colon of Th2-mediated experimental colitis model (Hokama et al., 2004). We herein demonstrate that the binding of galectin-4 is also intensified on CD4+ T cells, but not CD4− cell populations, in the inflamed colon of Th1-mediated colitis model (CD45RB model) as compared with those in the normal colon of WT mice (Fig. 1 A). In contrast, intensified binding of galectin-4 was not observed on CD4+ T cells in other tissues (lung and liver) of this colitis model (Fig. 1 B). To see whether the intensified galectin-4 binding on CD4+ T cells is a specific feature of colitis or a common feature associated with any inflammatory conditions, we next examined a concanavalin A–induced hepatitis model. Interestingly, binding of galectin-4 on CD4+ T cells was decreased in the inflamed liver (Fig. 1 B, right).


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)

CAG. (A) Galectin-4 (Gal4) binding patterns on lamina propria cells (including CD4+ versus CD4− cells) in normal colon of WT mice and inflamed colon of CD45RB model are shown. Data shown are one representation of seven independent experiments. (B) Intensities of galectin-4 binding on CD4+ T cells from the colon, lung, and liver of WT mouse, CD45RB model, and concanavalin A–induced hepatitis model (right panel) are shown. The results are representative in 3–12 mice in each group. (C) Intensities of galectin-3 (Gal3) and galectin-8 (Gal8) binding on CD4+ T cells from the colon of WT mouse and from the inflamed colon of CD45RB model are shown. The results are representative in 3 mice in each group. (D) Colonic tissues from healthy individuals (n = 5) and from patients with UC (n = 6), CD (n = 4), or Campylobacter infection (n = 2) were co-stained with FITC–anti-CD4 (green, left) and Alexa Fluor 594–labeled recombinant human galectin-4 (red, middle). Overlap images are shown on the right. Bars, 25 µm. (E) Flow cytometric analysis shows the intensity of galectin-4 binding on CD4+ (top) or CD8+ (bottom) T cells from inflamed colon (active, n = 10), noninvolved colon (inactive, n = 5), and peripheral blood (PBMC, n = 2) of UC patients and from normal colon of control subjects (normal, n = 4).
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig1: CAG. (A) Galectin-4 (Gal4) binding patterns on lamina propria cells (including CD4+ versus CD4− cells) in normal colon of WT mice and inflamed colon of CD45RB model are shown. Data shown are one representation of seven independent experiments. (B) Intensities of galectin-4 binding on CD4+ T cells from the colon, lung, and liver of WT mouse, CD45RB model, and concanavalin A–induced hepatitis model (right panel) are shown. The results are representative in 3–12 mice in each group. (C) Intensities of galectin-3 (Gal3) and galectin-8 (Gal8) binding on CD4+ T cells from the colon of WT mouse and from the inflamed colon of CD45RB model are shown. The results are representative in 3 mice in each group. (D) Colonic tissues from healthy individuals (n = 5) and from patients with UC (n = 6), CD (n = 4), or Campylobacter infection (n = 2) were co-stained with FITC–anti-CD4 (green, left) and Alexa Fluor 594–labeled recombinant human galectin-4 (red, middle). Overlap images are shown on the right. Bars, 25 µm. (E) Flow cytometric analysis shows the intensity of galectin-4 binding on CD4+ (top) or CD8+ (bottom) T cells from inflamed colon (active, n = 10), noninvolved colon (inactive, n = 5), and peripheral blood (PBMC, n = 2) of UC patients and from normal colon of control subjects (normal, n = 4).
Mentions: An endogenous glycan-binding protein family, the galectins, is composed of 15 members that recognize different carbohydrate epitopes and play different roles (e.g., anti- versus proinflammatory) in immune responses (Lowe, 2001; Baum and Crocker, 2009; Hsu et al., 2009; Rabinovich and Toscano, 2009). We previously demonstrated that an increased binding of galectin-4 is specifically seen on CD4+ T cells in the inflamed, but not normal, colon of Th2-mediated experimental colitis model (Hokama et al., 2004). We herein demonstrate that the binding of galectin-4 is also intensified on CD4+ T cells, but not CD4− cell populations, in the inflamed colon of Th1-mediated colitis model (CD45RB model) as compared with those in the normal colon of WT mice (Fig. 1 A). In contrast, intensified binding of galectin-4 was not observed on CD4+ T cells in other tissues (lung and liver) of this colitis model (Fig. 1 B). To see whether the intensified galectin-4 binding on CD4+ T cells is a specific feature of colitis or a common feature associated with any inflammatory conditions, we next examined a concanavalin A–induced hepatitis model. Interestingly, binding of galectin-4 on CD4+ T cells was decreased in the inflamed liver (Fig. 1 B, right).

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