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Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice.

Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA, Kunkel SL, Kung T, Wiekowski MT, Hedrick JA, Cook DN, Zingoni A, Narula SK, Zlotnik A, Barrat FJ, O'Garra A, Napolitano M, Lira SA - J. Exp. Med. (2001)

Bottom Line: In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency.Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5.These results indicate an important role for CCR8 in Th2 functional responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.

ABSTRACT
Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8(-/)- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo.

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Effect of CCR8 deletion on secondary type 1 (PPD) and type 2 (SEA) granuloma formation. Groups of CCR8+/+ (129 × B6) and CCR8−/− (129 × B6) mice were sensitized subcutaneously with M. bovis PPD in Freund's adjuvant or intraperitoneally with 3,000 S. mansoni eggs. After 14 d of sensitization, lung granulomas were elicited with 6,000 PPD or SEA Ag-coated beads. Granulomas were examined on day 4 after bead challenge. (Top left) Type 1 and type 2 granuloma cross-sectional areas. (Top right) Cellular composition of type 1 and type 2 lung granulomas. Five to six mice per group. (Bottom) Histologic appearances of type 2 (SEA) bead granulomas in CCR8+/+ and CCR8−/− (original magnifications: ×400; inset, ×800). All observations were repeated in three separate experiments. Bars are means ± SEM. *P < 0.05 comparing CCR8+/+ to CCR8−/−. Findings were similar in separate studies using either 129sv or 129sv × C57BL/6 F2 background mice. Lym, lymphocytes; Mac, macrophages; Eos, eosinophils; Neu, neutrophils.
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Figure 2: Effect of CCR8 deletion on secondary type 1 (PPD) and type 2 (SEA) granuloma formation. Groups of CCR8+/+ (129 × B6) and CCR8−/− (129 × B6) mice were sensitized subcutaneously with M. bovis PPD in Freund's adjuvant or intraperitoneally with 3,000 S. mansoni eggs. After 14 d of sensitization, lung granulomas were elicited with 6,000 PPD or SEA Ag-coated beads. Granulomas were examined on day 4 after bead challenge. (Top left) Type 1 and type 2 granuloma cross-sectional areas. (Top right) Cellular composition of type 1 and type 2 lung granulomas. Five to six mice per group. (Bottom) Histologic appearances of type 2 (SEA) bead granulomas in CCR8+/+ and CCR8−/− (original magnifications: ×400; inset, ×800). All observations were repeated in three separate experiments. Bars are means ± SEM. *P < 0.05 comparing CCR8+/+ to CCR8−/−. Findings were similar in separate studies using either 129sv or 129sv × C57BL/6 F2 background mice. Lym, lymphocytes; Mac, macrophages; Eos, eosinophils; Neu, neutrophils.

Mentions: Fig. 2, top left shows the effect of CCR8 deletion on day 4, type 1 (PPD), and type 2 (SEA) granuloma formation. Interestingly, CCR8 deletion had no significant effect on either type 1 or type 2 lesion cross sectional area. However, although type 1 lesions were histologically unchanged, the normally eosinophil-rich, type 2 lesions showed an apparent reduction in eosinophil content (Fig. 2, bottom). Quantitative analysis after enzymatic dispersal of lesions confirmed a significant abrogation of eosinophils (decreasing by 25 to 50% in three separate experiments). In contrast, type 1 lesion composition was unaffected by CCR8 deficiency (Fig. 2, top right).


Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice.

Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA, Kunkel SL, Kung T, Wiekowski MT, Hedrick JA, Cook DN, Zingoni A, Narula SK, Zlotnik A, Barrat FJ, O'Garra A, Napolitano M, Lira SA - J. Exp. Med. (2001)

Effect of CCR8 deletion on secondary type 1 (PPD) and type 2 (SEA) granuloma formation. Groups of CCR8+/+ (129 × B6) and CCR8−/− (129 × B6) mice were sensitized subcutaneously with M. bovis PPD in Freund's adjuvant or intraperitoneally with 3,000 S. mansoni eggs. After 14 d of sensitization, lung granulomas were elicited with 6,000 PPD or SEA Ag-coated beads. Granulomas were examined on day 4 after bead challenge. (Top left) Type 1 and type 2 granuloma cross-sectional areas. (Top right) Cellular composition of type 1 and type 2 lung granulomas. Five to six mice per group. (Bottom) Histologic appearances of type 2 (SEA) bead granulomas in CCR8+/+ and CCR8−/− (original magnifications: ×400; inset, ×800). All observations were repeated in three separate experiments. Bars are means ± SEM. *P < 0.05 comparing CCR8+/+ to CCR8−/−. Findings were similar in separate studies using either 129sv or 129sv × C57BL/6 F2 background mice. Lym, lymphocytes; Mac, macrophages; Eos, eosinophils; Neu, neutrophils.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193397&req=5

Figure 2: Effect of CCR8 deletion on secondary type 1 (PPD) and type 2 (SEA) granuloma formation. Groups of CCR8+/+ (129 × B6) and CCR8−/− (129 × B6) mice were sensitized subcutaneously with M. bovis PPD in Freund's adjuvant or intraperitoneally with 3,000 S. mansoni eggs. After 14 d of sensitization, lung granulomas were elicited with 6,000 PPD or SEA Ag-coated beads. Granulomas were examined on day 4 after bead challenge. (Top left) Type 1 and type 2 granuloma cross-sectional areas. (Top right) Cellular composition of type 1 and type 2 lung granulomas. Five to six mice per group. (Bottom) Histologic appearances of type 2 (SEA) bead granulomas in CCR8+/+ and CCR8−/− (original magnifications: ×400; inset, ×800). All observations were repeated in three separate experiments. Bars are means ± SEM. *P < 0.05 comparing CCR8+/+ to CCR8−/−. Findings were similar in separate studies using either 129sv or 129sv × C57BL/6 F2 background mice. Lym, lymphocytes; Mac, macrophages; Eos, eosinophils; Neu, neutrophils.
Mentions: Fig. 2, top left shows the effect of CCR8 deletion on day 4, type 1 (PPD), and type 2 (SEA) granuloma formation. Interestingly, CCR8 deletion had no significant effect on either type 1 or type 2 lesion cross sectional area. However, although type 1 lesions were histologically unchanged, the normally eosinophil-rich, type 2 lesions showed an apparent reduction in eosinophil content (Fig. 2, bottom). Quantitative analysis after enzymatic dispersal of lesions confirmed a significant abrogation of eosinophils (decreasing by 25 to 50% in three separate experiments). In contrast, type 1 lesion composition was unaffected by CCR8 deficiency (Fig. 2, top right).

Bottom Line: In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency.Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5.These results indicate an important role for CCR8 in Th2 functional responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.

ABSTRACT
Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8(-/)- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo.

Show MeSH
Related in: MedlinePlus