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Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection.

Booth JS, Salerno-Goncalves R, Blanchard TG, Patil SA, Kader HA, Safta AM, Morningstar LM, Czinn SJ, Greenwald BD, Sztein MB - Front Immunol (2015)

Bottom Line: We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity.Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals.However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues.

View Article: PubMed Central - PubMed

Affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Pediatrics, University of Maryland School of Medicine , Baltimore, MD , USA.

ABSTRACT
Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pylori - Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals. However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69(+) CD103(+)), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori.

No MeSH data available.


Responses of blood CD8+ MAIT cells from healthy adults to H. pylori-infected macrophages. (A) Representative volunteer showing the induction of cytokine production (IFN-γ, TNF-α, IL-17A) and up-regulation of CD107a expression by CD8+ MAIT cells following stimulation by H. pylori-infected differentiated THP-1 macrophages (Mϕ) at increasing effector to target (E:T) ratios (5:1, 10:1, 20:1, 50:1). (B) Cumulative data (n = 11) displaying the percentages of cytokine-producing and CD107a-expressing CD8+ MAIT cells following stimulation with H. pylori-infected Mϕ (E:T 5:1, 10:1, 20:1, 50:1), non-infected Mϕ, and effector cells alone. Shown are significant differences (*) between non-infected and infected targets. Significances were P < 0.0005 for CD107 and TNF-α and P < 0.005 for IFN-γ at all E:T ratios and P < 0.05 for IL-17A at 10:1, 20:1, and 50:1 E:T ratios. (C) Cumulative data (n = 11) showing cytokine production and expression of CD107a following stimulation with H. pylori-infected Mϕ at E:T (50:1) ratio, non-infected Mϕ, and effector cells alone. Horizontal black lines in (C) represent medians. Significant differences were determined between non-infected and H. pylori-infected Mϕ (*P < 0.05; **P < 0.005; ***P < 0.0005).
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Figure 3: Responses of blood CD8+ MAIT cells from healthy adults to H. pylori-infected macrophages. (A) Representative volunteer showing the induction of cytokine production (IFN-γ, TNF-α, IL-17A) and up-regulation of CD107a expression by CD8+ MAIT cells following stimulation by H. pylori-infected differentiated THP-1 macrophages (Mϕ) at increasing effector to target (E:T) ratios (5:1, 10:1, 20:1, 50:1). (B) Cumulative data (n = 11) displaying the percentages of cytokine-producing and CD107a-expressing CD8+ MAIT cells following stimulation with H. pylori-infected Mϕ (E:T 5:1, 10:1, 20:1, 50:1), non-infected Mϕ, and effector cells alone. Shown are significant differences (*) between non-infected and infected targets. Significances were P < 0.0005 for CD107 and TNF-α and P < 0.005 for IFN-γ at all E:T ratios and P < 0.05 for IL-17A at 10:1, 20:1, and 50:1 E:T ratios. (C) Cumulative data (n = 11) showing cytokine production and expression of CD107a following stimulation with H. pylori-infected Mϕ at E:T (50:1) ratio, non-infected Mϕ, and effector cells alone. Horizontal black lines in (C) represent medians. Significant differences were determined between non-infected and H. pylori-infected Mϕ (*P < 0.05; **P < 0.005; ***P < 0.0005).

Mentions: To investigate whether blood CD8+ MAIT cells could be efficiently stimulated by H. pylori-infected Mϕ, MAIT cells (effectors) were exposed to either non-infected Mϕ or H. pylori-infected Mϕ (targets) with increasing effector:target (E:T) ratios (5:1, 10:1, 20:1, and 50:1) and cytokine production and CD107a expression measured by flow cytometry. Following stimulation with H. pylori-infected THP-1 Mϕ, higher percentages of CD8+ MAIT cells producing cytokines (IFN-γ, IL-17A, and TNF-α) and up-regulating expression of CD107a were detected than stimulation with non-infected THP-1 Mϕ or effectors (Figure 3A). Cumulative data (n = 11) showed that significantly (P < 0.05) higher percentages of blood CD8+ MAIT cells produced cytokines (IFN-γ, IL-17A, and TNF-α) and expressed elevated levels of CD107a following stimulation with H. pylori-infected Mϕ than when exposed to non-infected Mϕ (Figures 3B,C).


Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection.

Booth JS, Salerno-Goncalves R, Blanchard TG, Patil SA, Kader HA, Safta AM, Morningstar LM, Czinn SJ, Greenwald BD, Sztein MB - Front Immunol (2015)

Responses of blood CD8+ MAIT cells from healthy adults to H. pylori-infected macrophages. (A) Representative volunteer showing the induction of cytokine production (IFN-γ, TNF-α, IL-17A) and up-regulation of CD107a expression by CD8+ MAIT cells following stimulation by H. pylori-infected differentiated THP-1 macrophages (Mϕ) at increasing effector to target (E:T) ratios (5:1, 10:1, 20:1, 50:1). (B) Cumulative data (n = 11) displaying the percentages of cytokine-producing and CD107a-expressing CD8+ MAIT cells following stimulation with H. pylori-infected Mϕ (E:T 5:1, 10:1, 20:1, 50:1), non-infected Mϕ, and effector cells alone. Shown are significant differences (*) between non-infected and infected targets. Significances were P < 0.0005 for CD107 and TNF-α and P < 0.005 for IFN-γ at all E:T ratios and P < 0.05 for IL-17A at 10:1, 20:1, and 50:1 E:T ratios. (C) Cumulative data (n = 11) showing cytokine production and expression of CD107a following stimulation with H. pylori-infected Mϕ at E:T (50:1) ratio, non-infected Mϕ, and effector cells alone. Horizontal black lines in (C) represent medians. Significant differences were determined between non-infected and H. pylori-infected Mϕ (*P < 0.05; **P < 0.005; ***P < 0.0005).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 3: Responses of blood CD8+ MAIT cells from healthy adults to H. pylori-infected macrophages. (A) Representative volunteer showing the induction of cytokine production (IFN-γ, TNF-α, IL-17A) and up-regulation of CD107a expression by CD8+ MAIT cells following stimulation by H. pylori-infected differentiated THP-1 macrophages (Mϕ) at increasing effector to target (E:T) ratios (5:1, 10:1, 20:1, 50:1). (B) Cumulative data (n = 11) displaying the percentages of cytokine-producing and CD107a-expressing CD8+ MAIT cells following stimulation with H. pylori-infected Mϕ (E:T 5:1, 10:1, 20:1, 50:1), non-infected Mϕ, and effector cells alone. Shown are significant differences (*) between non-infected and infected targets. Significances were P < 0.0005 for CD107 and TNF-α and P < 0.005 for IFN-γ at all E:T ratios and P < 0.05 for IL-17A at 10:1, 20:1, and 50:1 E:T ratios. (C) Cumulative data (n = 11) showing cytokine production and expression of CD107a following stimulation with H. pylori-infected Mϕ at E:T (50:1) ratio, non-infected Mϕ, and effector cells alone. Horizontal black lines in (C) represent medians. Significant differences were determined between non-infected and H. pylori-infected Mϕ (*P < 0.05; **P < 0.005; ***P < 0.0005).
Mentions: To investigate whether blood CD8+ MAIT cells could be efficiently stimulated by H. pylori-infected Mϕ, MAIT cells (effectors) were exposed to either non-infected Mϕ or H. pylori-infected Mϕ (targets) with increasing effector:target (E:T) ratios (5:1, 10:1, 20:1, and 50:1) and cytokine production and CD107a expression measured by flow cytometry. Following stimulation with H. pylori-infected THP-1 Mϕ, higher percentages of CD8+ MAIT cells producing cytokines (IFN-γ, IL-17A, and TNF-α) and up-regulating expression of CD107a were detected than stimulation with non-infected THP-1 Mϕ or effectors (Figure 3A). Cumulative data (n = 11) showed that significantly (P < 0.05) higher percentages of blood CD8+ MAIT cells produced cytokines (IFN-γ, IL-17A, and TNF-α) and expressed elevated levels of CD107a following stimulation with H. pylori-infected Mϕ than when exposed to non-infected Mϕ (Figures 3B,C).

Bottom Line: We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity.Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals.However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues.

View Article: PubMed Central - PubMed

Affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Pediatrics, University of Maryland School of Medicine , Baltimore, MD , USA.

ABSTRACT
Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pylori - Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals. However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69(+) CD103(+)), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori.

No MeSH data available.