Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic pressure and the breach of immunological self-tolerance


The prevalence of autoimmune disorders in affluent countries has reached epidemic proportions. Over the past 50 years, a reverse trend between the frequency of infectious diseases and the incidence of autoimmune and allergic diseases led to the so-called 'hygiene hypothesis'. Given the epidemiological evidence and recent experimental data, we propose that this concept should also include metabolic pressure secondary to exposure to excessive daily caloric intake and overnutrition. We discuss how metabolic workload can modulate immunological tolerance and review the molecular mechanisms and the state of the art of the field. We also critically evaluate possibilities for restoring immunological homeostasis under conditions of metabolic pressure.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Increased incidence of autoimmunity in affluent countries according to the hygiene hypothesis and the concept of early metabolic pressure and overload.
Figure 2: Metabolic pressure and immunotolerance to self.
Figure 3: Metabolic differences between Treg cells and Tconv cells, and Treg cells as metabolic sensors.


  1. 1

    McFarlane, H. Cell-mediated immunity in protein-calorie malnutrition. Lancet 2, 1146–1147 (1971).

    CAS  PubMed  Google Scholar 

  2. 2

    Bhargava, A. Undernutrition, nutritionally acquired immunodeficiency, and tuberculosis control. Br. Med. J. 355, i5407 (2016).

    Google Scholar 

  3. 3

    Lord, G.M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).

    CAS  PubMed  Google Scholar 

  4. 4

    Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    PubMed  Google Scholar 

  5. 5

    Ehlers, S. & Kaufmann, S.H. Infection, inflammation, and chronic diseases: consequences of a modern lifestyle. Trends Immunol. 31, 184–190 (2010).

    CAS  PubMed  Google Scholar 

  6. 6

    Matarese, G. & La Cava, A. The intricate interface between immune system and metabolism. Trends Immunol. 25, 193–200 (2004).

    CAS  PubMed  Google Scholar 

  7. 7

    Procaccini, C., Galgani, M., De Rosa, V. & Matarese, G. Intracellular metabolic pathways control immune tolerance. Trends Immunol. 33, 1–7 (2012).

    CAS  PubMed  Google Scholar 

  8. 8

    Cooper, G.S., Bynum, M.L. & Somers, E.C. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun. 33, 197–207 (2009).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Lerner, A., Jeremias, P. & Matthias, T. The world incidence and prevalence of autoimmune diseases is increasing. Int. J. Celiac. Dis. 3, 151–155 (2015).

    Google Scholar 

  10. 10

    Theofilopoulos, A.N., Kono, D.H. & Baccala, R. The multiple pathways to autoimmunity. Nat. Immunol. 18, 716–724 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    United States Department of Agriculture (USDA)–Economic Research Service. Food availability (per capita) data system (2016).

  12. 12

    Selmi, C. The worldwide gradient of autoimmune conditions. Autoimmun. Rev. 9, A247–A250 (2010).

    PubMed  Google Scholar 

  13. 13

    Manzel, A. et al. Role of “Western diet” in inflammatory autoimmune diseases. Curr. Allergy Asthma Rep. 14, 404 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Odegaard, J.I. & Chawla, A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb. Perspect. Med. 2, a007724 (2012).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Harpsøe, M.C. et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int. J. Epidemiol. 43, 843–855 (2014).

    PubMed  Google Scholar 

  16. 16

    Williams, E.P., Mesidor, M., Winters, K., Dubbert, P.M. & Wyatt, S.B. Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Curr. Obes. Rep. 4, 363–370 (2015).

    PubMed  Google Scholar 

  17. 17

    Darmawan, J., Muirden, K.D., Valkenburg, H.A. & Wigley, R.D. The epidemiology of rheumatoid arthritis in Indonesia. Br. J. Rheumatol. 32, 537–540 (1993).

    CAS  PubMed  Google Scholar 

  18. 18

    Friedman, J.M. The alphabet of weight control. Nature 385, 119–120 (1997).

    CAS  PubMed  Google Scholar 

  19. 19

    Hill, J.O. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr. Rev. 27, 750–761 (2006).

    PubMed  Google Scholar 

  20. 20

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Prentice, A.M. The thymus: a barometer of malnutrition. Br. J. Nutr. 81, 345–347 (1999).

    CAS  PubMed  Google Scholar 

  22. 22

    Howard, J.K. et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104, 1051–1059 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Di Rosa, F. & Gebhardt, T. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells. Front. Immunol. 7, 51 (2016).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Versini, M., Jeandel, P.Y., Rosenthal, E. & Shoenfeld, Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun. Rev. 13, 981–1000 (2014).

    CAS  PubMed  Google Scholar 

  25. 25

    Ferrara, C.T. et al. Type 1 Diabetes TrialNet Study Group. Excess BMI in childhood: a modifiable risk factor for type 1 diabetes development? Diabetes Care 40, 698–701 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 26

    Fourlanos, S., Harrison, L.C. & Colman, P.G. The accelerator hypothesis and increasing incidence of type 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 15, 321–325 (2008).

    CAS  PubMed  Google Scholar 

  27. 27

    Fourlanos, S. et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31, 1546–1549 (2008).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Mokry, L.E. et al. Obesity and multiple sclerosis: A mendelian randomization study. PLoS Med. 13, e1002053 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Sterry, W., Strober, B.E. & Menter, A. Obesity in psoriasis: the metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br. J. Dermatol. 157, 649–655 (2007).

    CAS  PubMed  Google Scholar 

  30. 30

    Procaccini, C. et al. Obesity and susceptibility to autoimmune diseases. Expert Rev. Clin. Immunol. 7, 287–294 (2011).

    CAS  PubMed  Google Scholar 

  31. 31

    Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Winer, S. et al. Obesity predisposes to Th17 bias. Eur. J. Immunol. 39, 2629–2635 (2009).

    CAS  PubMed  Google Scholar 

  33. 33

    Galgani, M. & Matarese, G. Editorial: acute inflammation in obesity: IL-17A in the middle of the battle. J. Leukoc. Biol. 87, 17–18 (2010).

    CAS  PubMed  Google Scholar 

  34. 34

    Kono, D.H. & Theofilopoulos, A.N. Autoimmunity. In:. Kelley and Firestein's Textbook of Rheumatology 10th edn. (eds. Firestein, G.S., Budd, R.C., Gabriel, S.E., McInnes, I.B. & O'Dell, J.R.) 2, 301–317 (Elsevier, Philadelphia, 2017).

    Google Scholar 

  35. 35

    Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Winer, D.A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Arai, S. et al. Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells. Cell Reports 3, 1187–1198 (2013).

    CAS  PubMed  Google Scholar 

  39. 39

    Kurien, B.T., Hensley, K., Bachmann, M. & Scofield, R.H. Oxidatively modified autoantigens in autoimmune diseases. Free Radic. Biol. Med. 41, 549–556 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    Saxton, R.A. & Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Efeyan, A., Comb, W.C. & Sabatini, D.M. Nutrient-sensing mechanisms and pathways. Nature 517, 302–310 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Delgoffe, G.M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Kim, J.S. et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat. Immunol. 14, 611–618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Park, Y. et al. TSC1 regulates the balance between effector and regulatory T cells. J. Clin. Invest. 123, 5165–5178 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Huynh, A. et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Gerriets, V.A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    De Rosa, V. et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 16, 1174–1184 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hawse, W.F., Boggess, W.C. & Morel, P.A. TCR signal strength regulates Akt substrate specificity to induce alternate murine Th and T regulatory cell differentiation programs. J. Immunol. 199, 589–597 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Turner, M.S., Kane, L.P. & Morel, P.A. Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J. Immunol. 183, 4895–4903 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Turner, M.S., Isse, K., Fischer, D.K., Turnquist, H.R. & Morel, P.A. Low TCR signal strength induces combined expansion of Th2 and regulatory T cell populations that protect mice from the development of type 1 diabetes. Diabetologia 57, 1428–1436 (2014).

    CAS  PubMed  Google Scholar 

  53. 53

    Miskov-Zivanov, N., Turner, M.S., Kane, L.P., Morel, P.A. & Faeder, J.R. The duration of T cell stimulation is a critical determinant of cell fate and plasticity. Sci. Signal. 6, ra97 (2013).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    He, X. et al. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci. Rep. 7, 43003 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Sabbatini, M. et al. Oscillatory mTOR inhibition and Treg increase in kidney transplantation. Clin. Exp. Immunol. 182, 230–240 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Ersching, J. et al. Germinal center selection and affinity maturation require dynamic regulation of mTORC1 kinase. Immunity 46, 1045–1058 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase ACC1. Cell Reports 12, 1042–1055 (2015).

    CAS  PubMed  Google Scholar 

  58. 58

    Reis, B.S. et al. Leptin receptor signaling in T cells is required for Th17 differentiation. J. Immunol. 194, 5253–5260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Stelzner, K. et al. Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses. Eur. J. Immunol. 46, 2043–2053 (2016).

    CAS  PubMed  Google Scholar 

  60. 60

    Daley, S.R. et al. Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies. eLife 2, e01020 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. 61

    Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).

    CAS  PubMed  Google Scholar 

  62. 62

    Shevach, E.M. & Thornton, A.M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259, 88–102 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Kaur, G., Goodall, J.C., Jarvis, L.B. & Hill Gaston, J.S. Characterisation of Foxp3 splice variants in human CD4+ and CD8+ T cells–identification of Foxp3Δ7 in human regulatory T cells. Mol. Immunol. 48, 321–332 (2010).

    CAS  PubMed  Google Scholar 

  64. 64

    Smith, E.L., Finney, H.M., Nesbitt, A.M., Ramsdell, F. & Robinson, M.K. Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation. Immunology 119, 203–211 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Allan, S.E. et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276–3284 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Vukmanovic-Stejic, M. et al. Human CD4+CD2hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J. Clin. Invest. 116, 2423–2433 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Vukmanovic-Stejic, M. et al. The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo. J. Clin. Invest. 118, 3639–3650 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Zhu, J. & Shevach, E.M. TCR signaling fuels Treg cell suppressor function. Nat. Immunol. 15, 1002–1003 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Procaccini, C. et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44, 406–421 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    De Rosa, V. et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26, 241–255 (2007).

    CAS  PubMed  Google Scholar 

  71. 71

    Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Naito, M. et al. Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice. Diabetes 60, 2265–2273 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Perry, R.J., Petersen, K.F. & Shulman, G.I. Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis. Diabetologia 59, 933–937 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Scudellari, M. News Feature: Cleaning up the hygiene hypothesis. Proc. Natl. Acad. Sci. USA 114, 1433–1436 (2017).

    CAS  PubMed  Google Scholar 

  76. 76

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Netea, M.G. et al. Trained immunity: A program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    PubMed  PubMed Central  Google Scholar 

  78. 78

    Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 1551 (2016).

    CAS  PubMed  Google Scholar 

  79. 79

    Pross, H.F. & Eidinger, D. Antigenic competition: a review of nonspecific antigen-induced suppression. Adv. Immunol. 18, 133–168 (1974).

    CAS  PubMed  Google Scholar 

  80. 80

    Serreze, D.V. & Leiter, E.H. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr. Opin. Immunol. 6, 900–906 (1994).

    CAS  PubMed  Google Scholar 

  81. 81

    Delovitch, T.L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

    CAS  PubMed  Google Scholar 

  82. 82

    Candon, S. et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS One 10, e0125448 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Brown, K. et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J. 10, 321–332 (2016).

    CAS  PubMed  Google Scholar 

  84. 84

    Kostic, A.D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260–273 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Alam, C. et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 54, 1398–1406 (2011).

    CAS  PubMed  Google Scholar 

  86. 86

    Sadelain, M.W., Qin, H.Y., Lauzon, J. & Singh, B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39, 583–589 (1990).

    CAS  PubMed  Google Scholar 

  87. 87

    Qin, H.Y. & Singh, B. BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide. J. Autoimmun. 10, 271–278 (1997).

    CAS  PubMed  Google Scholar 

  88. 88

    Lehmann, D. & Ben-Nun, A. Bacterial agents protect against autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or Mycobacterium tuberculosis are highly refractory to induction of experimental autoimmune encephalomyelitis. J. Autoimmun. 5, 675–690 (1992).

    CAS  PubMed  Google Scholar 

  89. 89

    Ben-Nun, A., Yossefi, S. & Lehmann, D. Protection against autoimmune disease by bacterial agents. II. PPD and pertussis toxin as proteins active in protecting mice against experimental autoimmune encephalomyelitis. Eur. J. Immunol. 23, 689–696 (1993).

    CAS  PubMed  Google Scholar 

  90. 90

    Ben-Nun, A., Mendel, I., Sappler, G. & Kerlero de Rosbo, N. A 12-kDa protein of Mycobacterium tuberculosis protects mice against experimental autoimmune encephalomyelitis. Protection in the absence of shared T cell epitopes with encephalitogenic proteins. J. Immunol. 154, 2939–2948 (1995).

    CAS  PubMed  Google Scholar 

  91. 91

    Carbone, F. et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat. Med. 20, 69–74 (2014).

    CAS  PubMed  Google Scholar 

  92. 92

    Kim, J.W. & Dang, C.V. Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142–150 (2005).

    CAS  PubMed  Google Scholar 

  93. 93

    Yang, Z., Fujii, H., Mohan, S.V., Goronzy, J.J. & Weyand, C.M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Melis, D. et al. Cutting edge: increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T cells and an impaired regulatory T cell function. J. Immunol. 198, 3803–3808 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Kim, J.G. et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908–910 (2014).

    CAS  PubMed  Google Scholar 

  96. 96

    Matarese, G. et al. Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc. Natl. Acad. Sci. USA 110, 6193–6198 (2013).

    CAS  PubMed  Google Scholar 

  97. 97

    Kuchroo, V.K. & Nicholson, L.B. Immunology: Fast and feel good? Nature 422, 27–28 (2003).

    CAS  PubMed  Google Scholar 

  98. 98

    Sanna, V. et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J. Clin. Invest. 111, 241–250 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Choi, I.Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Reports 15, 2136–2146 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    O'Neill, L.A. & Hardie, D.G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    CAS  PubMed  Google Scholar 

Download references


We thank S. Bruzzaniti for manuscript editing. This work is dedicated to the memory of Eugenia Papa and Serafino Zappacosta. Supported by the European Research Council (“menTORingTregs” grant 310496 to G.M.), the Fondazione Italiana Sclerosi Multipla (2016/R/18 to G.M. and 2014/R/21 to V.D.R.), Telethon (GGP17086 to G.M.), Associazione Italiana per la Ricerca sul Cancro-Cariplo TRansforming IDEas in Oncological Research (17447 to V.D.R.) and the US National Institutes of Health (AI109677 to A.L.C.).

Author information



Corresponding authors

Correspondence to Veronica De Rosa or Giuseppe Matarese.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

De Rosa, V., La Cava, A. & Matarese, G. Metabolic pressure and the breach of immunological self-tolerance. Nat Immunol 18, 1190–1196 (2017).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing