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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

Both Vγ1 and Vγ4 subset are involved in γδ T cell response to MCMV.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated days post-infection, 5–9 mice were sacrificed and immune cells were prepared from each organ. Expression of Vγ1, Vγ4 and Vγ7 chains by lymphocytes was evaluated by flow cytometry (S2 Fig.). A. Kinetics of absolute cell numbers for each subset. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by γδ T cell subsets was evaluated by flow cytometry 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.g005: Both Vγ1 and Vγ4 subset are involved in γδ T cell response to MCMV.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated days post-infection, 5–9 mice were sacrificed and immune cells were prepared from each organ. Expression of Vγ1, Vγ4 and Vγ7 chains by lymphocytes was evaluated by flow cytometry (S2 Fig.). A. Kinetics of absolute cell numbers for each subset. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by γδ T cell subsets was evaluated by flow cytometry 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: The subsets of murine γδ T lymphocytes expressing the Vγ1 or Vγ4 chains of the TCR predominate in the spleen, liver and lungs, whereas intestinal γδ T cells are almost exclusively Vγ7+ (nomenclature of Heilig and Tonegawa [29]). We assessed the quantity, repertoire and memory phenotype of these γδ T lymphocyte subsets in the liver, spleen and lungs. Not surprisingly, low proportions of Vγ1+ γδ T cells were found in the intestine (S2 Fig.). As observed in Fig. 5A, the expansion of γδ T cells in the lungs and liver after day 3 concerned mainly Vγ1+ but also Vγ4+ γδ T cells. Both subsets followed the kinetics of total γδ T cells (Fig. 4A). Analysis of subsets also showed a response of Vγ1+, but not Vγ4+ T cells, in the spleen (Fig. 4A and Fig. 5A). The proportion of EM cells among both Vγ1+ and Vγ4+ γδ T cells increased after day 3 in the lungs, liver and spleen (Fig. 5B). In contrast, Vγ7+ γδ T cell numbers/memory phenotype did not vary significantly upon MCMV infection (Fig. 5A and Fig. 5B), as could be expected from the analysis of the whole γδ T cell population in the intestine (Fig. 4A and Fig. 4C). The complementary-determining-region (CDR3)γ1 and CDR3γ4 length profile of liver, spleen and lung-derived γδ T cells were not different between uninfected and infected mice for 14 days (S3 Fig. and S4 Fig.), indicating that there were no major changes in these CDR3 repertoires after expansion.


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)

Both Vγ1 and Vγ4 subset are involved in γδ T cell response to MCMV.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated days post-infection, 5–9 mice were sacrificed and immune cells were prepared from each organ. Expression of Vγ1, Vγ4 and Vγ7 chains by lymphocytes was evaluated by flow cytometry (S2 Fig.). A. Kinetics of absolute cell numbers for each subset. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by γδ T cell subsets was evaluated by flow cytometry 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

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getmorefigures.php?uid=PMC4352080&req=5

ppat.1004702.g005: Both Vγ1 and Vγ4 subset are involved in γδ T cell response to MCMV.TCRα−/− mice were infected i.p. with 2.103 PFU of MCMV. At indicated days post-infection, 5–9 mice were sacrificed and immune cells were prepared from each organ. Expression of Vγ1, Vγ4 and Vγ7 chains by lymphocytes was evaluated by flow cytometry (S2 Fig.). A. Kinetics of absolute cell numbers for each subset. Presented data are mean ± SEM of 8–9 mice from one representative of 2 experiments. B. CD62L and CD44 expression by γδ T cell subsets was evaluated by flow cytometry 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: The subsets of murine γδ T lymphocytes expressing the Vγ1 or Vγ4 chains of the TCR predominate in the spleen, liver and lungs, whereas intestinal γδ T cells are almost exclusively Vγ7+ (nomenclature of Heilig and Tonegawa [29]). We assessed the quantity, repertoire and memory phenotype of these γδ T lymphocyte subsets in the liver, spleen and lungs. Not surprisingly, low proportions of Vγ1+ γδ T cells were found in the intestine (S2 Fig.). As observed in Fig. 5A, the expansion of γδ T cells in the lungs and liver after day 3 concerned mainly Vγ1+ but also Vγ4+ γδ T cells. Both subsets followed the kinetics of total γδ T cells (Fig. 4A). Analysis of subsets also showed a response of Vγ1+, but not Vγ4+ T cells, in the spleen (Fig. 4A and Fig. 5A). The proportion of EM cells among both Vγ1+ and Vγ4+ γδ T cells increased after day 3 in the lungs, liver and spleen (Fig. 5B). In contrast, Vγ7+ γδ T cell numbers/memory phenotype did not vary significantly upon MCMV infection (Fig. 5A and Fig. 5B), as could be expected from the analysis of the whole γδ T cell population in the intestine (Fig. 4A and Fig. 4C). The complementary-determining-region (CDR3)γ1 and CDR3γ4 length profile of liver, spleen and lung-derived γδ T cells were not different between uninfected and infected mice for 14 days (S3 Fig. and S4 Fig.), indicating that there were no major changes in these CDR3 repertoires after expansion.

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