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Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response

View Article: PubMed Central - PubMed

ABSTRACT

The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4+ T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4+ progenitor cells from infected hosts resulted in an increase DLL4+ myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis. We also found an increase in DLL4+ monocytes from individuals who were infected with Mycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4+ T cell responses to both previously encountered and novel antigens.

No MeSH data available.


Related in: MedlinePlus

Increased delta-like 4 expression in humans infected with Mtb. (A) Analysis of expression of DLL4 on CD14+ monocytes in individuals diagnosed with latent or active M. tuberculosis infection. (B) Flow cytometry plots gated on CD14+ monocytes, depicting dll4 expression of an individual treated for 6 months compared to an individual latently infected with Mtb. One-way ANOVA analysis indicated that DLL4 was expression was significantly altered during Mtb infection (p = 0.0044).
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Figure 3: Increased delta-like 4 expression in humans infected with Mtb. (A) Analysis of expression of DLL4 on CD14+ monocytes in individuals diagnosed with latent or active M. tuberculosis infection. (B) Flow cytometry plots gated on CD14+ monocytes, depicting dll4 expression of an individual treated for 6 months compared to an individual latently infected with Mtb. One-way ANOVA analysis indicated that DLL4 was expression was significantly altered during Mtb infection (p = 0.0044).

Mentions: We then hypothesized that expression of DLL4 could be detected on myeloid cells in the peripheral blood of humans with LTBI or active TB disease. As a negative control for these experiments, we used PPD negative healthy donors who were free of TB disease. Additionally, we tested those patients with active TB disease who had been successfully treated for 6 months with standard course anti-TB treatment. We found that those patients with LTBI or active TB disease had a significant increase in DLL4 expression when compared to both active TB patients following 6 months of treatment and normal healthy donors (Figure 3). When compared to normal healthy donors, this finding was statistically significant when we gated on CD14hi PBMCs [F(3,41) = 3.207, p = 0.0044]. Comparison of expression of DLL4 on total PBMCs in our cohort of patients also resulted in a statistical significance as determined by ANOVA [F(3,36) = 1.776, p = 0.02], but no significant differences were found using Tukey’s multiple comparison test.


Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response
Increased delta-like 4 expression in humans infected with Mtb. (A) Analysis of expression of DLL4 on CD14+ monocytes in individuals diagnosed with latent or active M. tuberculosis infection. (B) Flow cytometry plots gated on CD14+ monocytes, depicting dll4 expression of an individual treated for 6 months compared to an individual latently infected with Mtb. One-way ANOVA analysis indicated that DLL4 was expression was significantly altered during Mtb infection (p = 0.0044).
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Related In: Results  -  Collection

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Figure 3: Increased delta-like 4 expression in humans infected with Mtb. (A) Analysis of expression of DLL4 on CD14+ monocytes in individuals diagnosed with latent or active M. tuberculosis infection. (B) Flow cytometry plots gated on CD14+ monocytes, depicting dll4 expression of an individual treated for 6 months compared to an individual latently infected with Mtb. One-way ANOVA analysis indicated that DLL4 was expression was significantly altered during Mtb infection (p = 0.0044).
Mentions: We then hypothesized that expression of DLL4 could be detected on myeloid cells in the peripheral blood of humans with LTBI or active TB disease. As a negative control for these experiments, we used PPD negative healthy donors who were free of TB disease. Additionally, we tested those patients with active TB disease who had been successfully treated for 6 months with standard course anti-TB treatment. We found that those patients with LTBI or active TB disease had a significant increase in DLL4 expression when compared to both active TB patients following 6 months of treatment and normal healthy donors (Figure 3). When compared to normal healthy donors, this finding was statistically significant when we gated on CD14hi PBMCs [F(3,41) = 3.207, p = 0.0044]. Comparison of expression of DLL4 on total PBMCs in our cohort of patients also resulted in a statistical significance as determined by ANOVA [F(3,36) = 1.776, p = 0.02], but no significant differences were found using Tukey’s multiple comparison test.

View Article: PubMed Central - PubMed

ABSTRACT

The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4+ T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4+ progenitor cells from infected hosts resulted in an increase DLL4+ myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis. We also found an increase in DLL4+ monocytes from individuals who were infected with Mycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4+ T cell responses to both previously encountered and novel antigens.

No MeSH data available.


Related in: MedlinePlus