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γδ T cells confer protection against murine cytomegalovirus (MCMV).

Khairallah C, Netzer S, Villacreces A, Juzan M, Rousseau B, Dulanto S, Giese A, Costet P, Praloran V, Moreau JF, Dubus P, Vermijlen D, Déchanet-Merville J, Capone M - PLoS Pathog. (2015)

Bottom Line: As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells.This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells.Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients.

View Article: PubMed Central - PubMed

Affiliation: Université de Bordeaux, Bordeaux, France; CNRS, UMR 5164, Bordeaux, France.

ABSTRACT
Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αβ T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε-/- mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag-/-γc-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients.

No MeSH data available.


Related in: MedlinePlus

Mobilization of γδ T cells in MCMV-infected organs from TCRα−/− mice.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated post-infection days, 5–9 mice were sacrificed, immune cells prepared from each organ and γδ T cells stained as shown in S2 Fig.A. Kinetics of absolute γδ T cell numbers determined as described in methods. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by lymphocytes was evaluated by flow cytometry, with the presented gating strategy (lungs shown as example). C. Longitudinal analysis of γδ T cell phenotype in all organs. Results are pooled from 2 independent experiments representing a total of 13–14 mice (means ± SEM). Statistical differences of cell numbers and percentages between day 3 and other time points are shown, as well as statistical differences between days 0 and 56 (solid line).
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ppat.1004702.g004: Mobilization of γδ T cells in MCMV-infected organs from TCRα−/− mice.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated post-infection days, 5–9 mice were sacrificed, immune cells prepared from each organ and γδ T cells stained as shown in S2 Fig.A. Kinetics of absolute γδ T cell numbers determined as described in methods. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by lymphocytes was evaluated by flow cytometry, with the presented gating strategy (lungs shown as example). C. Longitudinal analysis of γδ T cell phenotype in all organs. Results are pooled from 2 independent experiments representing a total of 13–14 mice (means ± SEM). Statistical differences of cell numbers and percentages between day 3 and other time points are shown, as well as statistical differences between days 0 and 56 (solid line).

Mentions: We next sought to analyze whether the control of MCMV spread was associated with an amplification of γδ T cells in infected organs. S2 Fig. shows the gating strategy used for γδ T cell flow cytometry analysis. After a slight decrease at day 3, γδ T cell numbers increased importantly in the lungs until day 21 (approximately 8 fold), and this rise persisted until the end of the experiment. A significant but more modest and transient increase was also observed in the liver (approximately 2 fold from day 3 to 7). By contrast and to our surprise given their preponderance in gut intraepithelial lymphocytes, no significant variation of γδ T cells was observed in the intestine. In the spleen, γδ T cells levels remained stable until day 21 when they decreased (Fig. 4A). In conclusion, control of MCMV infection by γδ T cells in TCRα−/− mice is associated with a transient γδ T cell increase in the liver, and a delayed but strong and persistent expansion of γδ T cells in the lungs.


γδ T cells confer protection against murine cytomegalovirus (MCMV).

Khairallah C, Netzer S, Villacreces A, Juzan M, Rousseau B, Dulanto S, Giese A, Costet P, Praloran V, Moreau JF, Dubus P, Vermijlen D, Déchanet-Merville J, Capone M - PLoS Pathog. (2015)

Mobilization of γδ T cells in MCMV-infected organs from TCRα−/− mice.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated post-infection days, 5–9 mice were sacrificed, immune cells prepared from each organ and γδ T cells stained as shown in S2 Fig.A. Kinetics of absolute γδ T cell numbers determined as described in methods. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by lymphocytes was evaluated by flow cytometry, with the presented gating strategy (lungs shown as example). C. Longitudinal analysis of γδ T cell phenotype in all organs. Results are pooled from 2 independent experiments representing a total of 13–14 mice (means ± SEM). Statistical differences of cell numbers and percentages between day 3 and other time points are shown, as well as statistical differences between days 0 and 56 (solid line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352080&req=5

ppat.1004702.g004: Mobilization of γδ T cells in MCMV-infected organs from TCRα−/− mice.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated post-infection days, 5–9 mice were sacrificed, immune cells prepared from each organ and γδ T cells stained as shown in S2 Fig.A. Kinetics of absolute γδ T cell numbers determined as described in methods. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by lymphocytes was evaluated by flow cytometry, with the presented gating strategy (lungs shown as example). C. Longitudinal analysis of γδ T cell phenotype in all organs. Results are pooled from 2 independent experiments representing a total of 13–14 mice (means ± SEM). Statistical differences of cell numbers and percentages between day 3 and other time points are shown, as well as statistical differences between days 0 and 56 (solid line).
Mentions: We next sought to analyze whether the control of MCMV spread was associated with an amplification of γδ T cells in infected organs. S2 Fig. shows the gating strategy used for γδ T cell flow cytometry analysis. After a slight decrease at day 3, γδ T cell numbers increased importantly in the lungs until day 21 (approximately 8 fold), and this rise persisted until the end of the experiment. A significant but more modest and transient increase was also observed in the liver (approximately 2 fold from day 3 to 7). By contrast and to our surprise given their preponderance in gut intraepithelial lymphocytes, no significant variation of γδ T cells was observed in the intestine. In the spleen, γδ T cells levels remained stable until day 21 when they decreased (Fig. 4A). In conclusion, control of MCMV infection by γδ T cells in TCRα−/− mice is associated with a transient γδ T cell increase in the liver, and a delayed but strong and persistent expansion of γδ T cells in the lungs.

Bottom Line: As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells.This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells.Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients.

View Article: PubMed Central - PubMed

Affiliation: Université de Bordeaux, Bordeaux, France; CNRS, UMR 5164, Bordeaux, France.

ABSTRACT
Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αβ T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε-/- mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag-/-γc-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients.

No MeSH data available.


Related in: MedlinePlus