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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

γδ T cells prevent mice from MCMV-induced mortality.A. TCRδ−/−, TCRα−/− CD3ε+/− and CD3ε−/− mice (10 of each) were infected i.p. with 1.105 PFU of MCMV at day 0 and monitored every other day for mortality. Data are from one representative of 3 independent experiments. B. CD3ε+/− and CD3ε−/− mice (4 of each) were infected i.p. with indicated doses of MCMV at day 0 and monitored every day for mortality. Data are from one experiment.
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ppat.1004702.g001: γδ T cells prevent mice from MCMV-induced mortality.A. TCRδ−/−, TCRα−/− CD3ε+/− and CD3ε−/− mice (10 of each) were infected i.p. with 1.105 PFU of MCMV at day 0 and monitored every other day for mortality. Data are from one representative of 3 independent experiments. B. CD3ε+/− and CD3ε−/− mice (4 of each) were infected i.p. with indicated doses of MCMV at day 0 and monitored every day for mortality. Data are from one experiment.

Mentions: In mice, MCMV-specific αβ T cells control viral spread and protect infected mice from death [27] but little is known regarding the implication of γδ T cells. To evaluate the respective contribution of αβ and γδ T cells to the immune response against MCMV, mice deficient for γδ T cells (TCRδ−/−), for αβ T cells (TCRα−/−) or for both T cell subsets (CD3ε−/−) were challenged with 105 plaque forming units (PFU) of salivary gland MCMV. This dose was reported to be sublethal for C57BL/6 mice (as described at http://mutagenetix.utsouthwestern.edu/protocol/protocol_rec.cfm?protocolid=5). Accordingly, 100% of CD3ε+/− control mice survived MCMV infection, whereas CD3ε−/− died about 4 weeks after viral challenge (Fig. 1A), confirming the critical role of T cells in controlling MCMV infection. CD3ε−/− mice were extremely sensitive to MCMV despite the presence of NK cells [28] since they died at doses of MCMV as low as 2.103 PFU (Fig. 1B). Unexpectedly, both TCRδ−/− and TCRα−/− mice survived as long as CD3ε+/− control mice. These results reveal that the presence of either αβ or γδ T cell subset was sufficient to protect mice from MCMV infection, disclosing the potentially critical function of γδ T cells in the immune response against MCMV.


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)

γδ T cells prevent mice from MCMV-induced mortality.A. TCRδ−/−, TCRα−/− CD3ε+/− and CD3ε−/− mice (10 of each) were infected i.p. with 1.105 PFU of MCMV at day 0 and monitored every other day for mortality. Data are from one representative of 3 independent experiments. B. CD3ε+/− and CD3ε−/− mice (4 of each) were infected i.p. with indicated doses of MCMV at day 0 and monitored every day for mortality. Data are from one experiment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4352080&req=5

ppat.1004702.g001: γδ T cells prevent mice from MCMV-induced mortality.A. TCRδ−/−, TCRα−/− CD3ε+/− and CD3ε−/− mice (10 of each) were infected i.p. with 1.105 PFU of MCMV at day 0 and monitored every other day for mortality. Data are from one representative of 3 independent experiments. B. CD3ε+/− and CD3ε−/− mice (4 of each) were infected i.p. with indicated doses of MCMV at day 0 and monitored every day for mortality. Data are from one experiment.
Mentions: In mice, MCMV-specific αβ T cells control viral spread and protect infected mice from death [27] but little is known regarding the implication of γδ T cells. To evaluate the respective contribution of αβ and γδ T cells to the immune response against MCMV, mice deficient for γδ T cells (TCRδ−/−), for αβ T cells (TCRα−/−) or for both T cell subsets (CD3ε−/−) were challenged with 105 plaque forming units (PFU) of salivary gland MCMV. This dose was reported to be sublethal for C57BL/6 mice (as described at http://mutagenetix.utsouthwestern.edu/protocol/protocol_rec.cfm?protocolid=5). Accordingly, 100% of CD3ε+/− control mice survived MCMV infection, whereas CD3ε−/− died about 4 weeks after viral challenge (Fig. 1A), confirming the critical role of T cells in controlling MCMV infection. CD3ε−/− mice were extremely sensitive to MCMV despite the presence of NK cells [28] since they died at doses of MCMV as low as 2.103 PFU (Fig. 1B). Unexpectedly, both TCRδ−/− and TCRα−/− mice survived as long as CD3ε+/− control mice. These results reveal that the presence of either αβ or γδ T cell subset was sufficient to protect mice from MCMV infection, disclosing the potentially critical function of γδ T cells in the immune response against MCMV.

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