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Autophagy is essential for effector CD8(+) T cell survival and memory formation.

Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, Konieczny BT, Bruinsma MW, Martinez J, Pearce EL, Green DR, Jones DP, Virgin HW, Ahmed R - Nat. Immunol. (2014)

Bottom Line: In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase.Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells.Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.

View Article: PubMed Central - PubMed

Affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
The importance of autophagy in the generation of memory CD8(+) T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8(+) T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.

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Autophagy in CD8 T cells is essential for regulating chronic LCMV infection. Atg7fl/flGzmb-Cre and control Atg7fl/fl mice were infected with LCMV Clone-13. (a) Kinetics of DbGP276-specific T cells in the peripheral blood. (b) Total number of IFN-γ secreting cells in spleens after 5-hr stimulation ex vivo with peptide indicated from days 8 and 15 p.i. (c) Viral titers in serum at various time points p.i. n=3–5 mice in each group. Data are representative of two independent experiments. Error bars indicate SEM. *, p≤0.05; **, p≤0.005; ***p≤0.0005.
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Figure 8: Autophagy in CD8 T cells is essential for regulating chronic LCMV infection. Atg7fl/flGzmb-Cre and control Atg7fl/fl mice were infected with LCMV Clone-13. (a) Kinetics of DbGP276-specific T cells in the peripheral blood. (b) Total number of IFN-γ secreting cells in spleens after 5-hr stimulation ex vivo with peptide indicated from days 8 and 15 p.i. (c) Viral titers in serum at various time points p.i. n=3–5 mice in each group. Data are representative of two independent experiments. Error bars indicate SEM. *, p≤0.05; **, p≤0.005; ***p≤0.0005.

Mentions: Autophagy is required for memory CD8 T cell formation during an acute viral infection as shown above. Next, we asked whether autophagy regulates CD8 T cell responses during a chronic viral infection. To address this question, the Atg7fl/flGzmb-Cre mice were challenged with the LCMV Clone 13 strain, which causes a chronic infection31. In chronic infections antigen-specific T cells gradually diminish in their effector functionality and become exhausted cells due to prolonged persistence of antigen in the host32. During a chronic infection, antigen-specific CD8 T cells in the Atg7fl/flGzmb-Cre mice again mounted a initial response to the virus in the peripheral blood, as well as in lymphoid and non-lymphoid tissues at day 8 p.i., comparable to the wild-type controls (Fig. 8a, Supplementary Fig. 7a and b). Ex vivo stimulation of splenocytes at day 8 p.i. showed little difference in the number of cells producing IFN-γ (Fig. 8b). However, by day 15 p.i., most LCMV-specific T cells were lost in Atg7fl/flGzmb-Cre mice throughout lymphoid and non-lymphoid tissues, similar to the acute infection model (Fig. 8a, Supplementary Fig. 7c and d). The observed reduction was also reflected in the number of IFN-γ-producing cells when stimulated ex vivo (Fig. 8b). As a consequence of the loss of most antigen specific cells, viral control was compromised in Atg7fl/flGzmb-Cre mice (Fig. 8c). These data further indicated a significant survival defect in the Atg7-deficient LCMV-specific effector CD8 T cells; not only were these cells compromised in memory CD8 T cell differentiation, but they also failed to survive in the chronic infection model.


Autophagy is essential for effector CD8(+) T cell survival and memory formation.

Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, Konieczny BT, Bruinsma MW, Martinez J, Pearce EL, Green DR, Jones DP, Virgin HW, Ahmed R - Nat. Immunol. (2014)

Autophagy in CD8 T cells is essential for regulating chronic LCMV infection. Atg7fl/flGzmb-Cre and control Atg7fl/fl mice were infected with LCMV Clone-13. (a) Kinetics of DbGP276-specific T cells in the peripheral blood. (b) Total number of IFN-γ secreting cells in spleens after 5-hr stimulation ex vivo with peptide indicated from days 8 and 15 p.i. (c) Viral titers in serum at various time points p.i. n=3–5 mice in each group. Data are representative of two independent experiments. Error bars indicate SEM. *, p≤0.05; **, p≤0.005; ***p≤0.0005.
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Figure 8: Autophagy in CD8 T cells is essential for regulating chronic LCMV infection. Atg7fl/flGzmb-Cre and control Atg7fl/fl mice were infected with LCMV Clone-13. (a) Kinetics of DbGP276-specific T cells in the peripheral blood. (b) Total number of IFN-γ secreting cells in spleens after 5-hr stimulation ex vivo with peptide indicated from days 8 and 15 p.i. (c) Viral titers in serum at various time points p.i. n=3–5 mice in each group. Data are representative of two independent experiments. Error bars indicate SEM. *, p≤0.05; **, p≤0.005; ***p≤0.0005.
Mentions: Autophagy is required for memory CD8 T cell formation during an acute viral infection as shown above. Next, we asked whether autophagy regulates CD8 T cell responses during a chronic viral infection. To address this question, the Atg7fl/flGzmb-Cre mice were challenged with the LCMV Clone 13 strain, which causes a chronic infection31. In chronic infections antigen-specific T cells gradually diminish in their effector functionality and become exhausted cells due to prolonged persistence of antigen in the host32. During a chronic infection, antigen-specific CD8 T cells in the Atg7fl/flGzmb-Cre mice again mounted a initial response to the virus in the peripheral blood, as well as in lymphoid and non-lymphoid tissues at day 8 p.i., comparable to the wild-type controls (Fig. 8a, Supplementary Fig. 7a and b). Ex vivo stimulation of splenocytes at day 8 p.i. showed little difference in the number of cells producing IFN-γ (Fig. 8b). However, by day 15 p.i., most LCMV-specific T cells were lost in Atg7fl/flGzmb-Cre mice throughout lymphoid and non-lymphoid tissues, similar to the acute infection model (Fig. 8a, Supplementary Fig. 7c and d). The observed reduction was also reflected in the number of IFN-γ-producing cells when stimulated ex vivo (Fig. 8b). As a consequence of the loss of most antigen specific cells, viral control was compromised in Atg7fl/flGzmb-Cre mice (Fig. 8c). These data further indicated a significant survival defect in the Atg7-deficient LCMV-specific effector CD8 T cells; not only were these cells compromised in memory CD8 T cell differentiation, but they also failed to survive in the chronic infection model.

Bottom Line: In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase.Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells.Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.

View Article: PubMed Central - PubMed

Affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
The importance of autophagy in the generation of memory CD8(+) T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8(+) T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.

Show MeSH
Related in: MedlinePlus