Autophagy maintains metabolic order

Credit: S. Bradbrook/NPG

Autophagy is the process through which intracellular components are targeted to lysosomes for degradation and recycling — it is essential for maintaining cellular homeostasis, particularly during infection or metabolic stress. Two complementary studies describe a crucial role for autophagy in regulating cellular metabolism in regulatory T (T_Reg) cells and T helper 2 (T_H2) cells. Interestingly, defective autophagy impairs survival and lineage stability in peripheral T_Reg cells but leads to expansion of T_H2 cell populations in a cell-intrinsic manner.

Wei et al. found that peripheral T_Reg cells show higher autophagy activity compared with naive CD4⁺ T cells. They generated mice with a T_Reg cell-specific deletion of the essential autophagy-related 7 (Atg7) gene (Foxp3^CreAtg7^fl/fl mice) and found that these animals developed lymphoid hyperplasia by ∼3 months of age and had increased proportions of effector/memory T cells compared with controls. Effector/memory T cells from Foxp3^CreAtg7^fl/fl mice produced aberrantly high levels of interferon-γ (IFNγ) and interleukin-17 (IL-17), and the animals developed severe systemic inflammation by ∼5 months of age. Compared with controls, Foxp3^CreAtg7^fl/fl mice had lower proportions of T_Reg cells in the spleen, lymph nodes and, in particular, the colon but normal proportions of thymic T_Reg cells. Similar phenotypes were observed in mice with a T_Reg cell-specific deletion of Atg5, another essential autophagy gene.

Further analyses showed that ATG7 is not essential for T_Reg cell proliferation but instead promotes their survival and lineage stability. ATG7-deficient T_Reg cells showed higher rates of apoptosis and a failure to maintain FOXP3 expression, which was associated with the upregulation of IFNγ and other inflammatory cytokines. Autophagy maintained T_Reg cell stability and survival partly by restraining mTOR complex 1 (mTORC1) activity following T_Reg cell activation through T cell receptors or other stimulatory pathways. Aberrant mTORC1 activity in ATG7-deficient T_Reg cells was associated with increased MYC expression and heightened glycolytic metabolism; pharmacological blockade of MYC or glycolysis partially restored lineage stability in these cells. Furthermore, activated T_Reg cells were more sensitive to apoptosis than quiescent T_Reg cells in response to autophagy deficiency. Therefore, autophagy preferentially supports the survival and lineage stability of activated T_Reg cells.

Kabat et al. examined how the inflammatory bowel disease (IBD)-associated gene autophagy-related 16-like 1 (Atg16l1) affects intestinal T cell responses. They generated mice with a CD4⁺ T cell-specific deletion of Atg16l1 (Atg16l1^ΔCD4 mice) and found that these animals developed splenomegaly, lymphadenopathy and chronic intestinal pathology by ∼ 5 months of age. Younger Atg16l1^ΔCD4 mice had lower T cell counts in peripheral lymphoid organs and the intestine compared with controls, but developed exacerbated disease in a model of IBD. Closer analysis showed that young Atg16l1^ΔCD4 mice had decreased numbers of T_H1 and T_H17 cells, and reduced peripheral T_Reg cell counts (particularly in the intestine) but had higher T_H2 cell numbers. In keeping with this, ageing Atg16l1^ΔCD4 mice developed an aberrant type 2 antibody response against dietary antigens and commensal bacteria.

The authors found that T_Reg cells from Atg16l1^ΔCD4 mice showed intrinsic survival defects, whereas T_H2 cells from these animals showed comparable or improved survival in relation to wild-type controls. Experiments in which Atg16l1^ΔCD4 mice were reconstituted with wild-type T_Reg cells indicated that ATG16L1 regulates T_H2 cell expansion through a cell-intrinsic mechanism, rather than indirectly through T_Reg cell loss. Kabat et al. next generated mice with a T_Reg cell-specific deletion of Atg16l1 (Foxp3^CreAtg16l1^fl/fl mice); in agreement with the findings by Wei et al., these animals developed a severe spontaneous systemic inflammation by 5 months of age that was associated with impaired survival and lineage stability of peripheral T_Reg cells. Also in keeping with the study by Wei et al., Kabat et al. found that ATG16L1-deficient T_Reg cells showed augmented glycolytic activity; this was most apparent in intestinal T_Reg cells. The authors noted that T_H2 cells have enhanced glycolytic metabolism compared with T_Reg cells under homeostatic conditions and propose that this accounts for why T_H2 cells are more resistant to the metabolic consequences of blocking autophagy.

drugs targeting autophagy could be useful for manipulating peripheral CD4⁺ T cell responses in the clinic

These studies suggest that drugs targeting autophagy could be useful for manipulating peripheral CD4⁺ T cell responses in the clinic — indeed, in a mouse tumour model, Wei et al. observed that Foxp3^CreAtg7^fl/fl mice have reduced tumour cell growth owing to defective T_Reg cell function at the tumour site.