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Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium tuberculosis infection.

Obregón-Henao A, Henao-Tamayo M, Orme IM, Ordway DJ - PLoS ONE (2013)

Bottom Line: Both populations of Gr1(+)CD11b(+) cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells.Our results showed that both Gr1(hi) and Gr1(int) cells were able to induce activation and proliferation of CD4+ T cells.However this response was reduced as the ratio of CD4(+) T to Gr1(+) cells increased.

View Article: PubMed Central - PubMed

Affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.

ABSTRACT

Background: Tuberculosis is one of the world's leading killers, stealing 1.4 million lives and causing 8.7 million new and relapsed infections in 2011. The only vaccine against tuberculosis is BCG which demonstrates variable efficacy in adults worldwide. Human infection with Mycobacterium tuberculosis results in the influx of inflammatory cells to the lung in an attempt to wall off bacilli by forming a granuloma. Gr1(int)CD11b(+) cells are called myeloid-derived suppressor cells (MDSC) and play a major role in regulation of inflammation in many pathological conditions. Although MDSC have been described primarily in cancer their function in tuberculosis remains unknown. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation. Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design.

Methodology/principal findings: We compared the bacterial burden, lung pathology and Gr1(int)CD11b(+) myeloid-derived suppressor cell immune responses in M. tuberculosis infected NOS2-/-, RAG-/-, C3HeB/FeJ and C57/BL6 mice. Gr-1(+) cells could be found on the edges of necrotic lung lesions in NOS2-/-, RAG-/-, and C3HeB/FeJ, but were absent in wild-type mice. Both populations of Gr1(+)CD11b(+) cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells. We then sorted the Gr1(hi) and Gr1(int) populations from M. tuberculosis infected NOS-/- mice and placed the sorted both Gr1(int) populations at different ratios with naïve or M. tuberculosis infected splenocytes and evaluated their ability to induce activation and proliferation of CD4+T cells. Our results showed that both Gr1(hi) and Gr1(int) cells were able to induce activation and proliferation of CD4+ T cells. However this response was reduced as the ratio of CD4(+) T to Gr1(+) cells increased. Our results illustrate a yet unrecognized interplay between Gr1(+) cells and CD4(+) T cells in tuberculosis.

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Significant numbers of Gr1int CD11b+ cells were also found in RAG2-/- and C3HeB/FeJ mice.The influx of Gr1intCD11b+ cells was evaluated in immunocompromised RAG-/- (A), and immunocompetent C3HeB/FeJ mice (C) and NOS-/- (F). Again, large numbers of Gr1intCD11b+ cells were observed in these three mouse strains and significant differences were observed in the Gr1+ MFI (B, D, G). Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). In contrast, C3H/HeOuJ did not have major arginase activity. Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). Results are expressed as the mean values of mean fluorescence intensity (MFI) or arginase activity (± SEM, n=5) in the Lung. **Student t-test, p<0.001.
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pone-0080669-g005: Significant numbers of Gr1int CD11b+ cells were also found in RAG2-/- and C3HeB/FeJ mice.The influx of Gr1intCD11b+ cells was evaluated in immunocompromised RAG-/- (A), and immunocompetent C3HeB/FeJ mice (C) and NOS-/- (F). Again, large numbers of Gr1intCD11b+ cells were observed in these three mouse strains and significant differences were observed in the Gr1+ MFI (B, D, G). Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). In contrast, C3H/HeOuJ did not have major arginase activity. Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). Results are expressed as the mean values of mean fluorescence intensity (MFI) or arginase activity (± SEM, n=5) in the Lung. **Student t-test, p<0.001.

Mentions: Given these observations, we posed the question as to whether these observations were unique to the NOS2 -/- model, or were a common feature in models in which lung necrosis occurs. To address this question, we used immunocompetent C3HeB/FeJ mice and immunodeficient Rag2 -/- mice as additional possible examples, given the knowledge these both develop severe lung necrosis [19,30-32]. As shown in Figure 5, similar results were obtained in these C3HeB/FeJ (Figure 5A, B), Rag2 -/- (Figure 5C, D) and NOS-/- mice (Figure 5F, G). In infected Rag2 -/- mice a very prominent Gr-1intCD11b+ population was by far the largest (Figure 5A, B). In C3HeB/FeJ mice, two clearly distinct Gr1+ CD11b+ populations of relatively equal size were only observed in the necrotic-prone C3HeB/FeJ mice but not in control C3H/HeOuJ devoid of necrosis (Figure 5C, D). Lastly, in NOS-/- mice compared to wild-type mice two clearly distinct Gr1+ CD11b+ populations were observed with the Gr-1intCD11b+ population being larger than the Gr-hiCD11b+ (Figure 5F, G) population.


Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium tuberculosis infection.

Obregón-Henao A, Henao-Tamayo M, Orme IM, Ordway DJ - PLoS ONE (2013)

Significant numbers of Gr1int CD11b+ cells were also found in RAG2-/- and C3HeB/FeJ mice.The influx of Gr1intCD11b+ cells was evaluated in immunocompromised RAG-/- (A), and immunocompetent C3HeB/FeJ mice (C) and NOS-/- (F). Again, large numbers of Gr1intCD11b+ cells were observed in these three mouse strains and significant differences were observed in the Gr1+ MFI (B, D, G). Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). In contrast, C3H/HeOuJ did not have major arginase activity. Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). Results are expressed as the mean values of mean fluorescence intensity (MFI) or arginase activity (± SEM, n=5) in the Lung. **Student t-test, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815237&req=5

pone-0080669-g005: Significant numbers of Gr1int CD11b+ cells were also found in RAG2-/- and C3HeB/FeJ mice.The influx of Gr1intCD11b+ cells was evaluated in immunocompromised RAG-/- (A), and immunocompetent C3HeB/FeJ mice (C) and NOS-/- (F). Again, large numbers of Gr1intCD11b+ cells were observed in these three mouse strains and significant differences were observed in the Gr1+ MFI (B, D, G). Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). In contrast, C3H/HeOuJ did not have major arginase activity. Similar to NOS2 -/- mice, arginase activity was also increased in C3HeB/FeJ undergoing lung necrosis (E). Results are expressed as the mean values of mean fluorescence intensity (MFI) or arginase activity (± SEM, n=5) in the Lung. **Student t-test, p<0.001.
Mentions: Given these observations, we posed the question as to whether these observations were unique to the NOS2 -/- model, or were a common feature in models in which lung necrosis occurs. To address this question, we used immunocompetent C3HeB/FeJ mice and immunodeficient Rag2 -/- mice as additional possible examples, given the knowledge these both develop severe lung necrosis [19,30-32]. As shown in Figure 5, similar results were obtained in these C3HeB/FeJ (Figure 5A, B), Rag2 -/- (Figure 5C, D) and NOS-/- mice (Figure 5F, G). In infected Rag2 -/- mice a very prominent Gr-1intCD11b+ population was by far the largest (Figure 5A, B). In C3HeB/FeJ mice, two clearly distinct Gr1+ CD11b+ populations of relatively equal size were only observed in the necrotic-prone C3HeB/FeJ mice but not in control C3H/HeOuJ devoid of necrosis (Figure 5C, D). Lastly, in NOS-/- mice compared to wild-type mice two clearly distinct Gr1+ CD11b+ populations were observed with the Gr-1intCD11b+ population being larger than the Gr-hiCD11b+ (Figure 5F, G) population.

Bottom Line: Both populations of Gr1(+)CD11b(+) cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells.Our results showed that both Gr1(hi) and Gr1(int) cells were able to induce activation and proliferation of CD4+ T cells.However this response was reduced as the ratio of CD4(+) T to Gr1(+) cells increased.

View Article: PubMed Central - PubMed

Affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.

ABSTRACT

Background: Tuberculosis is one of the world's leading killers, stealing 1.4 million lives and causing 8.7 million new and relapsed infections in 2011. The only vaccine against tuberculosis is BCG which demonstrates variable efficacy in adults worldwide. Human infection with Mycobacterium tuberculosis results in the influx of inflammatory cells to the lung in an attempt to wall off bacilli by forming a granuloma. Gr1(int)CD11b(+) cells are called myeloid-derived suppressor cells (MDSC) and play a major role in regulation of inflammation in many pathological conditions. Although MDSC have been described primarily in cancer their function in tuberculosis remains unknown. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation. Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design.

Methodology/principal findings: We compared the bacterial burden, lung pathology and Gr1(int)CD11b(+) myeloid-derived suppressor cell immune responses in M. tuberculosis infected NOS2-/-, RAG-/-, C3HeB/FeJ and C57/BL6 mice. Gr-1(+) cells could be found on the edges of necrotic lung lesions in NOS2-/-, RAG-/-, and C3HeB/FeJ, but were absent in wild-type mice. Both populations of Gr1(+)CD11b(+) cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells. We then sorted the Gr1(hi) and Gr1(int) populations from M. tuberculosis infected NOS-/- mice and placed the sorted both Gr1(int) populations at different ratios with naïve or M. tuberculosis infected splenocytes and evaluated their ability to induce activation and proliferation of CD4+T cells. Our results showed that both Gr1(hi) and Gr1(int) cells were able to induce activation and proliferation of CD4+ T cells. However this response was reduced as the ratio of CD4(+) T to Gr1(+) cells increased. Our results illustrate a yet unrecognized interplay between Gr1(+) cells and CD4(+) T cells in tuberculosis.

Show MeSH
Related in: MedlinePlus