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CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo.

Lloyd CM, Delaney T, Nguyen T, Tian J, Martinez-A C, Coyle AJ, Gutierrez-Ramos JC - J. Exp. Med. (2000)

Bottom Line: Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells.We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway.We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

View Article: PubMed Central - PubMed

Affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. c.lloyd@ic.ac.uk

ABSTRACT
Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

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CCR3/eotaxin and CCR4/MDC function in a coordinated manner to promote Th2 cell recruitment in vivo. Numbers of total CD4 cells and antigen-specific donor Th cells were counted in mice treated with neutralizing Ab (stippled bars) or control Ab (white bars) after transfer of Th2 (A) or Th1 (B) cells. The percentage of antigen-specific cells was quantified by counting at least 250 CD4+ cells in each section, and then counting the number of KJ126+ cells in serial sections at a magnification of 400 for 10 mice in each group from two separate experiments (i). Total numbers of CD4+ cells per hpf are shown (ii).
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Figure 3: CCR3/eotaxin and CCR4/MDC function in a coordinated manner to promote Th2 cell recruitment in vivo. Numbers of total CD4 cells and antigen-specific donor Th cells were counted in mice treated with neutralizing Ab (stippled bars) or control Ab (white bars) after transfer of Th2 (A) or Th1 (B) cells. The percentage of antigen-specific cells was quantified by counting at least 250 CD4+ cells in each section, and then counting the number of KJ126+ cells in serial sections at a magnification of 400 for 10 mice in each group from two separate experiments (i). Total numbers of CD4+ cells per hpf are shown (ii).

Mentions: We have found previously that the antieotaxin and anti-MDC Abs used in this study block the specific migration of CCR3- or CCR4-expressing cells, both in vitro and in vivo 713. Mice were killed on day 4 or 7, and the migration of antigen-specific Th cells to the lung was determined histologically. The donor Th1 and Th2 cells expressed a clonotypic TCR recognized by an mAb, making it possible to distinguish donor (antigen-specific) cells from host Th cells 17. We found that although the total number of CD4 cells was unaffected by blockage of either CCR3 or CCR4 ligands, the percentage of antigen-specific Th2 cells decreased by at least 50% (Fig. 3). In contrast, blockage of eotaxin or MDC had no effect on the migration of antigen-specific Th1 cells (Fig. 3 B). However, the specific effect of blocking one pathway versus the other differed at each time point (as discussed in detail below). These data show that eotaxin and MDC interactions with their specific receptors in vivo are critical for antigen-specific Th2 cell recruitment to the lung in this model.


CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo.

Lloyd CM, Delaney T, Nguyen T, Tian J, Martinez-A C, Coyle AJ, Gutierrez-Ramos JC - J. Exp. Med. (2000)

CCR3/eotaxin and CCR4/MDC function in a coordinated manner to promote Th2 cell recruitment in vivo. Numbers of total CD4 cells and antigen-specific donor Th cells were counted in mice treated with neutralizing Ab (stippled bars) or control Ab (white bars) after transfer of Th2 (A) or Th1 (B) cells. The percentage of antigen-specific cells was quantified by counting at least 250 CD4+ cells in each section, and then counting the number of KJ126+ cells in serial sections at a magnification of 400 for 10 mice in each group from two separate experiments (i). Total numbers of CD4+ cells per hpf are shown (ii).
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Related In: Results  -  Collection

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Figure 3: CCR3/eotaxin and CCR4/MDC function in a coordinated manner to promote Th2 cell recruitment in vivo. Numbers of total CD4 cells and antigen-specific donor Th cells were counted in mice treated with neutralizing Ab (stippled bars) or control Ab (white bars) after transfer of Th2 (A) or Th1 (B) cells. The percentage of antigen-specific cells was quantified by counting at least 250 CD4+ cells in each section, and then counting the number of KJ126+ cells in serial sections at a magnification of 400 for 10 mice in each group from two separate experiments (i). Total numbers of CD4+ cells per hpf are shown (ii).
Mentions: We have found previously that the antieotaxin and anti-MDC Abs used in this study block the specific migration of CCR3- or CCR4-expressing cells, both in vitro and in vivo 713. Mice were killed on day 4 or 7, and the migration of antigen-specific Th cells to the lung was determined histologically. The donor Th1 and Th2 cells expressed a clonotypic TCR recognized by an mAb, making it possible to distinguish donor (antigen-specific) cells from host Th cells 17. We found that although the total number of CD4 cells was unaffected by blockage of either CCR3 or CCR4 ligands, the percentage of antigen-specific Th2 cells decreased by at least 50% (Fig. 3). In contrast, blockage of eotaxin or MDC had no effect on the migration of antigen-specific Th1 cells (Fig. 3 B). However, the specific effect of blocking one pathway versus the other differed at each time point (as discussed in detail below). These data show that eotaxin and MDC interactions with their specific receptors in vivo are critical for antigen-specific Th2 cell recruitment to the lung in this model.

Bottom Line: Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells.We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway.We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

View Article: PubMed Central - PubMed

Affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. c.lloyd@ic.ac.uk

ABSTRACT
Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

Show MeSH
Related in: MedlinePlus