Immune Dysfunction as a Cause and Consequence of Malnutrition
Authors: Claire D. Bourke, James A. Berkley, Andrew J. Prendergast
Journal: Trends in Immunology (2016)

Undernourished children principally die of common infections, and immune defects are consistently demonstrated in under- and overnutrition. Parental malnutrition leads to epigenetic modifications of infant immune and metabolic genes. Healthy gut development relies on sensing of dietary nutrients, commensal, and pathogenic microbes via immune receptors. Recurrent infections, chronic inflammation, and enteropathy compound clinical malnutrition by altering gut structure and function. Immune cell activation and systemic proinflammatory mediator levels are increased in malnutrition. Malnutrition impairs immune priming by DC and monocytes, and impairs effector memory T cell function. Immune dysfunction can directly drive pathological processes in malnutrition, including malabsorption, increased metabolic demand, dysregulation of the growth hormone and HPA axes, and greater susceptibility to infection. Malnutrition, which encompasses under- and overnutrition, is responsible for an enormous morbidity and mortality burden globally. Malnutrition results from disordered nutrient assimilation but is also characterized by recurrent infections and chronic inflammation, implying an underlying immune defect. Defects emerge before birth via modifications in the immunoepigenome of malnourished parents, and these may contribute to intergenerational cycles of malnutrition. This review summarizes key recent studies from experimental animals, in vitro models, and human cohorts, and proposes that immune dysfunction is both a cause and a consequence of malnutrition. Focusing on childhood undernutrition, we highlight gaps in current understanding of immune dysfunction in malnutrition, with a view to therapeutically targeting immune pathways as a novel means to reduce morbidity and mortality. Malnutrition, which encompasses under- and overnutrition, is responsible for an enormous morbidity and mortality burden globally. Malnutrition results from disordered nutrient assimilation but is also characterized by recurrent infections and chronic inflammation, implying an underlying immune defect. Defects emerge before birth via modifications in the immunoepigenome of malnourished parents, and these may contribute to intergenerational cycles of malnutrition. This review summarizes key recent studies from experimental animals, in vitro models, and human cohorts, and proposes that immune dysfunction is both a cause and a consequence of malnutrition. Focusing on childhood undernutrition, we highlight gaps in current understanding of immune dysfunction in malnutrition, with a view to therapeutically targeting immune pathways as a novel means to reduce morbidity and mortality. Malnutrition, which encompasses both under- and overnutrition, is responsible for an enormous health burden globally [1Rahman S.A. Adjeroh D. Surface-based body shape index and its relationship with all-cause mortality.PLoS ONE. 2015; 10: e0144639Crossref PubMed Scopus (26) Google Scholar, 2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar] (Box 1). Although broadly defined as impaired nutrient assimilation, malnutrition does not simply arise from inadequate food intake. Obesity can develop independently of poor diet and persist despite switching to a healthy diet [3Clemente J.C. et al.The impact of the gut microbiota on human health: an integrative view.Cell. 2012; 148: 1258-1270Abstract Full Text Full Text PDF PubMed Scopus (2263) Google Scholar, 4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 5Godfrey K.M. et al.Epigenetic gene promoter methylation at birth is associated with child's later adiposity.Diabetes. 2011; 60: 1528-1534Crossref PubMed Scopus (576) Google Scholar, 6Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2502) Google Scholar, 7van der Klaauw A.A. Farooqi I.S. The hunger genes: pathways to obesity.Cell. 2015; 161: 119-132Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar], and stunting prevalence is only modestly reduced by intensive feeding interventions [8Bhutta Z.A. et al.What works? Interventions for maternal and child undernutrition and survival.Lancet. 2008; 371: 417-440Abstract Full Text Full Text PDF PubMed Scopus (1416) Google Scholar]. Despite manifesting as distinct physical defects, several observations implicate shared etiological pathways in under- and overnutrition: early-life undernutrition increases the risk of obesity in later life [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 9Roseboom T. et al.The Dutch famine and its long-term consequences for adult health.Early Hum. 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Hyg. 2013; 88: 390-396Crossref PubMed Scopus (224) Google Scholar], and gut dysfunction (enteropathy) [11Kong L.C. et al.Dietary patterns differently associate with inflammation and gut microbiota in overweight and obese subjects.PLoS ONE. 2014; 9: e109434Crossref PubMed Scopus (95) Google Scholar, 12O'Keefe S.J.D. et al.Fat, fibre and cancer risk in African Americans and rural Africans.Nat. Commun. 2015; 6: 6342Crossref PubMed Scopus (589) Google Scholar, 16Subramanian S. et al.Persistent gut microbiota immaturity in malnourished Bangladeshi children.Nature. 2014; 510: 417-421Crossref PubMed Scopus (745) Google Scholar] are features of both conditions; and excess energy and macronutrient intake is often coincident with micronutrient deficiencies in overweight individuals [17Pereira-Santos M. et al.Obesity and vitamin D deficiency: a systematic review and meta-analysis.Obes. Rev. 2015; 16: 341-349Crossref PubMed Scopus (485) Google Scholar, 18Sanchez A. et al.Micronutrient deficiencies in morbidly obese women prior to bariatric surgery.Obes. Surg. 2016; 26: 361-368Crossref PubMed Scopus (73) Google Scholar]. There is a growing appreciation that malnutrition is complex, reflecting a suite of overlapping comorbidities that are poorly understood [19Humphrey J.H. Child undernutrition, tropical enteropathy, toilets, and handwashing.Lancet. 2009; 374: 1032-1035Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar, 21Ahmed T. et al.An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome.Ann. N. Y. Acad. Sci. 2014; 1332: 22-38Crossref PubMed Scopus (39) Google Scholar]. Characterizing pathogenesis across the spectrum of malnutrition is essential to underpin novel therapeutic approaches to support international goals to improve nutrition, health, and well-being (https://sustainabledevelopment.un.org).Box 1Epidemiology and Clinical Features of MalnutritionMalnutrition is a clinical syndrome that encompasses a spectrum of anthropometric defects from wasting (low weight-for-height) and stunting (low height-for-age) in undernutrition to overweight (body mass index, BMI, of 25–30) and obesity (BMI >30) in overnutrition. An estimated 3.1 million children under 5 years die annually as a result of undernutrition, accounting for 45% of all child mortality [2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar]. The global prevalence of overweight in the under 5 year age group increased by 54% between 1990 and 2011 [2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar].Growth faltering in developing countries is often evident at birth. Weight-for-age and length-for-age Z scores continue to decline over the first 2 years of life, with little recovery thereafter [70Victora C.G. et al.Worldwide timing of growth faltering: revisiting implications for interventions.Pediatrics. 2010; 125: e473-e480Crossref PubMed Scopus (891) Google Scholar]. Maternal height and infant birthweight are consistent predictors of infant growth (short mothers bear small babies who become stunted adults themselves) [20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar]. Stunting affects around 165 million children worldwide (www.who.int/nutgrowthdb/estimates/en) and is associated with short-term increases in infectious mortality and long-term neurodevelopmental defects [20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar, 65Marques A.H. et al.The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders.Front. Neurosci. 2013; 7: 120Crossref PubMed Scopus (142) Google Scholar, 87Fernald L.C. Grantham-McGregor S.M. Stress response in school-age children who have been growth retarded since early childhood.Am. J. Clin. Nutr. 1998; 68: 691-698Crossref PubMed Scopus (72) Google Scholar]. Stunted children are shorter than healthy reference populations (height-for-age Z score ≤2) and may exhibit reduced exploratory behavior and physiological arousal [87Fernald L.C. Grantham-McGregor S.M. Stress response in school-age children who have been growth retarded since early childhood.Am. J. Clin. Nutr. 1998; 68: 691-698Crossref PubMed Scopus (72) Google Scholar], but are otherwise clinically well.Wasting affects approximately 52 million children (www.who.int/nutgrowthdb/estimates/en) and has a stronger association with case mortality than stunting. Wasting is characterized by loss of fat and muscle in the thighs, buttocks, upper arms, and ribs; severe acute malnutrition (SAM) is characterized by severe wasting (mid-upper arm circumference (MUAC) <115 mm for children aged 6–59 months and/or weight-for-height Z score ≤3; www.who.int/childgrowth/standards). Kwashiorkor is a distinct SAM phenotype typified by skin and hair changes, irritability, symmetrical edema, and fatty liver infiltration. Children with uncomplicated SAM (no apparent infections and good appetite) can be managed in the community with energy-dense micronutrient-supplemented foods [84WHOManagement of the Child with a Serious Infection or Severe Malnutrition: Guidelines for Care at the First-Referral Level in Developing Countries. World Health Organisation, 2000Google Scholar]. Children with complicated SAM (clinically unwell and/or refusing feeds) are often physiologically unstable, with impaired organ function, coinfections, micronutrient deficiencies, and a high risk of dying, which requires immediate hospitalization, supervised feeding and rehydration, and broad-spectrum antibiotics even if symptoms of infection are absent [84WHOManagement of the Child with a Serious Infection or Severe Malnutrition: Guidelines for Care at the First-Referral Level in Developing Countries. World Health Organisation, 2000Google Scholar].Early-life undernutrition confers an increased risk of obesity in adulthood [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 9Roseboom T. et al.The Dutch famine and its long-term consequences for adult health.Early Hum. Dev. 2006; 82: 485-491Crossref PubMed Scopus (712) Google Scholar]. This 'double burden' of malnutrition disproportionately affects low- and middle-income countries undergoing rapid socioeconomic changes [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar]. Clinical symptoms of obesity include high percentage adipose tissue, high circulating levels of triglycerides, high blood pressure which can lead to cardiovascular disease, and high blood glucose levels reflecting insulin resistance which can lead to type-2 diabetes [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 6Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2502) Google Scholar, 9Roseboom T. et al.The Dutch famine and its long-term consequences for adult health.Early Hum. Dev. 2006; 82: 485-491Crossref PubMed Scopus (712) Google Scholar, 25Huttunen R. Syrjanen J. Obesity and the risk and outcome of infection.Int. J. Obes. (Lond). 2013; 37: 333-340Crossref PubMed Scopus (373) Google Scholar]. Similarly to undernutrition, overweight is associated with an increased risk of all-cause [1Rahman S.A. Adjeroh D. Surface-based body shape index and its relationship with all-cause mortality.PLoS ONE. 2015; 10: e0144639Crossref PubMed Scopus (26) Google Scholar] and infectious mortality [25Huttunen R. Syrjanen J. Obesity and the risk and outcome of infection.Int. J. Obes. (Lond). 2013; 37: 333-340Crossref PubMed Scopus (373) Google Scholar]. Malnutrition is a clinical syndrome that encompasses a spectrum of anthropometric defects from wasting (low weight-for-height) and stunting (low height-for-age) in undernutrition to overweight (body mass index, BMI, of 25–30) and obesity (BMI >30) in overnutrition. An estimated 3.1 million children under 5 years die annually as a result of undernutrition, accounting for 45% of all child mortality [2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar]. The global prevalence of overweight in the under 5 year age group increased by 54% between 1990 and 2011 [2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar]. Growth faltering in developing countries is often evident at birth. Weight-for-age and length-for-age Z scores continue to decline over the first 2 years of life, with little recovery thereafter [70Victora C.G. et al.Worldwide timing of growth faltering: revisiting implications for interventions.Pediatrics. 2010; 125: e473-e480Crossref PubMed Scopus (891) Google Scholar]. Maternal height and infant birthweight are consistent predictors of infant growth (short mothers bear small babies who become stunted adults themselves) [20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar]. Stunting affects around 165 million children worldwide (www.who.int/nutgrowthdb/estimates/en) and is associated with short-term increases in infectious mortality and long-term neurodevelopmental defects [20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar, 65Marques A.H. et al.The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders.Front. Neurosci. 2013; 7: 120Crossref PubMed Scopus (142) Google Scholar, 87Fernald L.C. Grantham-McGregor S.M. Stress response in school-age children who have been growth retarded since early childhood.Am. J. Clin. Nutr. 1998; 68: 691-698Crossref PubMed Scopus (72) Google Scholar]. Stunted children are shorter than healthy reference populations (height-for-age Z score ≤2) and may exhibit reduced exploratory behavior and physiological arousal [87Fernald L.C. Grantham-McGregor S.M. Stress response in school-age children who have been growth retarded since early childhood.Am. J. Clin. Nutr. 1998; 68: 691-698Crossref PubMed Scopus (72) Google Scholar], but are otherwise clinically well. Wasting affects approximately 52 million children (www.who.int/nutgrowthdb/estimates/en) and has a stronger association with case mortality than stunting. Wasting is characterized by loss of fat and muscle in the thighs, buttocks, upper arms, and ribs; severe acute malnutrition (SAM) is characterized by severe wasting (mid-upper arm circumference (MUAC) <115 mm for children aged 6–59 months and/or weight-for-height Z score ≤3; www.who.int/childgrowth/standards). Kwashiorkor is a distinct SAM phenotype typified by skin and hair changes, irritability, symmetrical edema, and fatty liver infiltration. Children with uncomplicated SAM (no apparent infections and good appetite) can be managed in the community with energy-dense micronutrient-supplemented foods [84WHOManagement of the Child with a Serious Infection or Severe Malnutrition: Guidelines for Care at the First-Referral Level in Developing Countries. World Health Organisation, 2000Google Scholar]. Children with complicated SAM (clinically unwell and/or refusing feeds) are often physiologically unstable, with impaired organ function, coinfections, micronutrient deficiencies, and a high risk of dying, which requires immediate hospitalization, supervised feeding and rehydration, and broad-spectrum antibiotics even if symptoms of infection are absent [84WHOManagement of the Child with a Serious Infection or Severe Malnutrition: Guidelines for Care at the First-Referral Level in Developing Countries. World Health Organisation, 2000Google Scholar]. Early-life undernutrition confers an increased risk of obesity in adulthood [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 9Roseboom T. et al.The Dutch famine and its long-term consequences for adult health.Early Hum. Dev. 2006; 82: 485-491Crossref PubMed Scopus (712) Google Scholar]. This 'double burden' of malnutrition disproportionately affects low- and middle-income countries undergoing rapid socioeconomic changes [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar]. Clinical symptoms of obesity include high percentage adipose tissue, high circulating levels of triglycerides, high blood pressure which can lead to cardiovascular disease, and high blood glucose levels reflecting insulin resistance which can lead to type-2 diabetes [4DeBoer M.D. et al.Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?.Nutr. Rev. 2012; 70: 642-653Crossref PubMed Scopus (105) Google Scholar, 6Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2502) Google Scholar, 9Roseboom T. et al.The Dutch famine and its long-term consequences for adult health.Early Hum. Dev. 2006; 82: 485-491Crossref PubMed Scopus (712) Google Scholar, 25Huttunen R. Syrjanen J. Obesity and the risk and outcome of infection.Int. J. Obes. (Lond). 2013; 37: 333-340Crossref PubMed Scopus (373) Google Scholar]. Similarly to undernutrition, overweight is associated with an increased risk of all-cause [1Rahman S.A. Adjeroh D. Surface-based body shape index and its relationship with all-cause mortality.PLoS ONE. 2015; 10: e0144639Crossref PubMed Scopus (26) Google Scholar] and infectious mortality [25Huttunen R. Syrjanen J. Obesity and the risk and outcome of infection.Int. J. Obes. (Lond). 2013; 37: 333-340Crossref PubMed Scopus (373) Google Scholar]. Undernourished children principally die of common infections [22Bryce J. et al.WHO estimates of the causes of death in children.Lancet. 2005; 365: 1147-1152Abstract Full Text Full Text PDF PubMed Scopus (1504) Google Scholar, 23Rytter M.J.H. et al.The immune system in children with malnutrition–a systematic review.PLoS ONE. 2014; 9: e105017Crossref PubMed Scopus (313) Google Scholar], implying that mortality is related to underlying immunodeficiency, even in mild forms of undernutrition [24Olofin I. et al.Associations of suboptimal growth with all-cause and cause-specific mortality in children under five years: a pooled analysis of ten prospective studies.PLoS ONE. 2013; : 8Google Scholar]. Infections are more common and more severe in people with obesity [25Huttunen R. Syrjanen J. Obesity and the risk and outcome of infection.Int. J. Obes. (Lond). 2013; 37: 333-340Crossref PubMed Scopus (373) Google Scholar]. Defects in both the innate and adaptive arms of the immune system have been consistently demonstrated in undernourished children (Box 2) [23Rytter M.J.H. et al.The immune system in children with malnutrition–a systematic review.PLoS ONE. 2014; 9: e105017Crossref PubMed Scopus (313) Google Scholar]. In this review we explore the hypothesis that immune dysfunction is both a cause and consequence of malnutrition, and summarize key recent evidence from experimental animal models, human cohorts, and in vitro studies. We regard malnutrition as a syndrome in which multiple underlying processes are the cause of elevated mortality and morbidity [20Prendergast A.J. Humphrey J.H. The stunting syndrome in developing countries.Paediatr. Int. Child Health. 2014; 34: 250-265Crossref PubMed Scopus (454) Google Scholar] (Box 1); immune dysfunction is involved in many of these pathways and is therefore a key driver of the vicious cycle that leads to clinical malnutrition (Figure 1). Our focus is childhood undernutrition in developing countries, where the greatest burden of mortality is concentrated [2Black R.E. et al.Maternal and child undernutrition and overweight in low-income and middle-income countries.Lancet. 2013; 382: 427-451Abstract Full Text Full Text PDF PubMed Scopus (4271) Google Scholar], but we also identify relevant studies of overnutrition. Throughout the review we highlight research gaps that need to be addressed in future studies and speculate on the potential for immune-targeted therapies to reduce morbidity and mortality in undernourished children.Box 2Immune Defects in Undernourished ChildrenA recent systematic literature review [23Rytter M.J.H. et al.The immune system in children with malnutrition–a systematic review.PLoS ONE. 2014; 9: e105017Crossref PubMed Scopus (313) Google Scholar] identified 245 studies published between 1957 and 2014 describing immune parameters in undernourished children (age 0–5 years). However, the review highlights that the majority of studies were conducted several decades ago using out-dated immunology techniques and focused on hospitalized children with severe forms of malnutrition and multiple coinfections. Characterization of immunodeficiency was limited by a lack of longitudinal studies, particularly for mild and moderate malnutrition. The precise nature of immunodeficiency in undernutrition therefore remains uncertain; however, the consensus from the available evidence is that both innate and adaptive immunity are impaired by malnutrition. Defects in innate immune function include impaired epithelial barrier function of the skin and gut, reduced granulocyte microbicidal activity, fewer circulating dendritic cells, and reduced complement proteins, but preserved leukocyte numbers and acute phase response. Defects in adaptive immune function include reduced levels of soluble IgA in saliva and tears, lymphoid organ atrophy, reduced delayed-type hypersensitivity responses, fewer circulating B cells, a shift from Th1-associated to Th2-associated cytokines, and lymphocyte hyporesponsiveness to phytohemagglutinin, but preserved lymphocyte and immunoglobulin levels in peripheral blood. Despite this, most malnourished children seem to respond adequately to vaccination, although the timing, quality, and longevity of vaccine-specific responses may be impaired [71Prendergast A.J. Malnutrition and vaccination in developing countries.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; : 370Google Scholar, 72Savy M. et al.Landscape analysis of interactions between nutrition and vaccine responses in children.J. Nutr. 2009; 139: 2154s-2218sCrossref PubMed Scopus (106) Google Scholar].There is an evident need for contemporary studies of childhood undernutrition incorporating up-to-date functional immunological methods in well-characterized longitudinal cohorts of children. Studies need to define malnutrition using current metrics of stunting, wasting, or both together, with appropriate well-nourished comparison groups, and evaluate associations between immune parameters and clinical outcomes. Development of novel experimental approaches to explore immune ontogeny [88Thome J.J.C. et al.Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.Nat. 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Commun. 2015; 6: 7806Crossref PubMed Scopus (131) Google Scholar], and nutrient-sensing [38Veldhoen M. Ferreira C. Influence of nutrient-derived metabolites on lymphocyte immunity.Nat. Med. 2015; 21: 709-718Crossref PubMed Scopus (43) Google Scholar, 39Li Y. et al.Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.Cell. 2011; 147: 629-640Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar] also provide unprecedented opportunities for translation into immunological studies of childhood undernutrition. Because immunodeficiency is also a feature of overnutrition (reviewed recently [6Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 2