Journal Club

Research Highlights

CD8+ T cells showed increased Finally, the authors generated production of IFNγ and TNF mixed bone marrow chimeric when activated in vitro. Expression mice with T cells that were only analysis confirmed that there CYPD-deficient or wild-type T cells. Journal club was no difference in the levels of Five weeks after infection, there was apoptosis markers in T cells from significantly higher proliferation and Starvation suppresses T cell appetite CYPD-deficient mice or wild-type IFNγ production by CYPD-deficient mice. Thus, these results suggest T cells than wild-type T cells in The world is inhabited by more than 7.6 billion people, that increased proliferation, and not the lungs, suggesting that CYPD of whom one in nine suffer chronic undernourishment or reduced cell death, explained the intrinsically regulates T cell responses starvation. How this ‘nutrient-restricted’ situation affects higher number of CYPD-deficient to infection. Consistent with this immune function had not, until recently, been investigated. T cells in the lungs of infected mice. observation, temporary depletion Indeed, little thought had been given to how the biochemical Given the localization of CYPD in of T cells in CYPD-deficient mice changes that occur under conditions of nutrient stress mitochondria, the authors examined prolonged their survival following translate to fundamental changes in immune cells and their whether CYPD affected the metabolic infection. Furthermore, the survival capacity to generate antibodies or effector and memory activity of T cells. Bioenergetic flux of RAG1-deficient mice reconstituted cells for protection. A study published by Iyer et al. in 2012 analysis showed that both aerobic with CYPD-deficient T cells was changed all that. glycolysis and mitochondrial oxidative significantly reduced compared with Although it had already been recognized that phosphorylation were elevated in those receiving wild-type T cells. malnutrition is associated with poor vaccine responses, CYPD-deficient T cells compared with This study shows that although Iyer et al. linked cellular nutrient levels in immune cells wild-type T cells. The enhanced T cell T cell responses are crucial for host to the ability of cytotoxic T cells to mount a vigorous activation and proliferation seemed to defence against M. tuberculosis response to a challenge. The group discovered that be regulated by mitochondrial reactive infection, T cell hyperproliferation chronic malnutrition limited the ability of the immune oxygen species (mROS), as mROS and hyperactivation compromises system to either replenish key cellular compartments levels were higher in CYPD-deficient TB disease tolerance. through homeostatic proliferation or recruit + CD8 T cells than in wild-type T cells, Grant Otto antigen-specific memory T cells into a secondary response, and quenching mROS blocked Original article Tzelepis, F. et al. two essential functions that are required for long-lived the increased proliferation and the Mitochondrial cyclophilin D regulates T cell immune protection. Thus, the fate of immune cells — in this metabolic responses and disease tolerance to aberrant metabolic activity of + tuberculosis. Sci. Immunol. 3, eaar4135 (2018) case, CD8 T cells — is strongly determined by their CYPD-deficient T cells. metabolism, which directly influences immune health. The study also showed that immune cell metabolism depends on the protein and energy supplies in the diet Next, the authors showed that a high- Finally, the authors assessed and that this could be manipulated to improve immune fibre diet did not affect neutrophil whether the antiviral T cell response development but altered haematopoiesis was affected by dietary fibre. They outcomes. by increasing macrophage precursors noted that antiviral CD8+ T cells were The work of Iyer et al. provided a first clue to how in the bone marrow. This led to an more activated, had greater cytotoxic different metabolic products in cells affect their increase in the frequency of Ly6C– capacity and accumulated in higher development, maintenance and protective functions. patrolling monocytes relative to Ly6C+ numbers in the lungs of mice on a In exciting developments extending from this landmark inflammatory monocytes in the bone high-fibre diet than those of mice on paper, it is now recognized that the metabolic and signalling marrow and lungs after infection. Mice a control diet. Indeed, these effects requirements of T cells are interlinked. This affects both fed a high-fibre diet or given butyrate could be seen in vitro after culturing T cell fate and their capacity to reprogramme their had more interstitial and alveolar CD8+ T cells in the presence of functions to deal with particular types of infection. macrophages following infection, and butyrate, suggesting a direct effect The metabolic programme of immune cells has also been these macrophages had an alternative of SCFAs on T cells, probably through found to influence the outcome of diseases such as obesity, activation profile. The generation of FFAR3. The more activated phenotype diabetes and cancer. The oversupply of nutrients also alternatively activated macrophages of CD8+ T cells in mice on a high-fibre affects immune cell function and can itself contribute to (AAMs) was mediated by SCFAs acting diet was associated with multiple different types of disease. Collectively, these studies have on FFAR3 expressed by macrophage alterations in T cell metabolism, led to an entirely new direction in immunological research. precursors, as only wild-type precursors including increased glycolytic rate, Emerging exciting questions will impact our understanding –/– mitochondrial mass and capacity for and not Ffar3 precursors in chimeric not only of immune cell function, but also of disease oxidative phosphorylation. mice led to an accumulation of lung processes, and potentially uncover new therapeutic leads So, a high-fibre diet protects against AAMs in response to butyrate and for treatment. infection. AAMs are less capable of influenza virus by shaping monocyte producing the neutrophil chemoattractant development, to limit immunopathology, Gabrielle Belz + CXCL1 than classically activated and CD8 T cell metabolism, to enhance Walter and Eliza Hall Institute of Medical Research, and The University of Melbourne, macrophages. Accordingly, airway antiviral immunity. Lucy Bird Melbourne, Australia. CXCL1 levels in infected mice on a high- e-mail: [email protected] The author declares no competing interests. fibre diet were lower than those in infected Original article Trompette, A. et al. Dietary animals on a control diet, thereby linking fibre confers protection against flu by shaping the altered macrophage phenotype to the Ly6c– patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 48, 992–1005 (2018) Original article Iyer, S. S. et al. Protein energy malnutrition impairs homeostatic diminished neutrophil response. proliferation of memory CD8 T cells. J. Immunol. 188, 77–84 (2012)