Obesity Expands a Distinct Population of T Cells in Adipose Tissue and Increases Vulnerability to Infection
Ichiro Misumi, Joshua Starmer, Toru Uchimura, Melinda A Beck, Terry Magnuson, Jason K Whitmire, Ichiro Misumi, Joshua Starmer, Toru Uchimura, Melinda A Beck, Terry Magnuson, Jason K Whitmire
Abstract
Obesity in humans is associated with poorer health outcomes after infections compared with non-obese individuals. Here, we examined the effects of white adipose tissue and obesity on T cell responses to viral infection in mice. We show that lymphocytic choriomeningitis virus (LCMV) grows to high titer in adipose tissue. Virus-specific T cells enter the adipose tissue to resolve infection but then remain as a memory population distinct from memory T cells in lymphoid tissues. Memory T cells in adipose tissue are abundant in lean mice, and diet-induced obesity further increases memory T cell number in adipose tissue and spleen. Upon re-challenge infection, memory T cells rapidly cause severe pathogenesis, leading to increases in lipase levels, calcification of adipose tissue, pancreatitis, and reduced survival in obese mice but not lean mice. Thus, obesity leads to a unique form of viral pathogenesis involving memory T cell-dependent adipocyte destruction and damage to other tissues.
Keywords: LCMV; T cell memory; Trm; obesity; pancreatitis; tissue-resident memory T cells; white adipose tissue.
Conflict of interest statement
DECLARATION OF INTERESTS
The authors declare no competing interests.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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References
- Ahmed A, Azim A, Gurjar M, and Baronia AK (2016). Hypocalcemia in acute pancreatitis revisited. Indian J. Crit. Care Med 20, 173–177.
- Anderson KG, Mayer-Barber K, Sung H, Beura L, James BR, Taylor JJ, Qunaj L, Griffith TS, Vezys V, Barber DL, and Masopust D (2014). Intravascular staining for discrimination of vascular and tissue leukocytes. Nat. Protoc 9, 209–222.
- Barnes MA, Carson MJ, and Nair MG (2015). Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system. Cytokine 72, 210–219.
- Chen AT, Cornberg M, Gras S, Guillonneau C, Rossjohn J, Trees A, Emonet S, de la Torre JC, Welsh RM, and Selin LK (2012). Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. PLoS Pathog 8, e1002633.
- Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, and Obin MS (2005). Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res 46, 2347–2355.
- Couturier J, Suliburk JW, Brown JM, Luke DJ, Agarwal N, Yu X, Nguyen C, Iyer D, Kozinetz CA, Overbeek PA, et al. (2015). Human adipose tissue as a reservoir for memory CD4+ T cells and HIV. AIDS 29, 667–674.
- Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, Ren Y, Yin Z, Hamilton DJ, Reardon PR, et al. (2013). Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 17, 411–422.
- Dettelbach MA, Deftos LJ, and Stewart AF (1990). Intraperitoneal free fatty acids induce severe hypocalcemia in rats: a model for the hypocalcemia of pancreatitis. J. Bone Miner. Res 5, 1249–1255.
- Díaz E, Rodríguez A, Martin-Loeches I, Lorente L, Del Mar Martín M, Pozo JC, Montejo JC, Estella A, Arenzana Á , and Rello J; H1N1 SEMICYUC Working Group (2011). Impact of obesity in patients infected with 2009 influenza A(H1N1). Chest 139, 382–386.
- Gerlach C, Moseman EA, Loughhead SM, Alvarez D, Zwijnenburg AJ, Waanders L, Garg R, de la Torre JC, and von Andrian UH (2016). The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284.
- Grant RW, and Dixit VD (2015). Adipose tissue as an immunological organ. Obesity (Silver Spring) 23, 512–518.
- Grant R, Youm YH, Ravussin A, and Dixit VD (2013). Quantification of adipose tissue leukocytosis in obesity. Methods Mol. Biol 1040, 195–209.
- Han SJ, Glatman Zaretsky A, Andrade-Oliveira V, Collins N, Dzutsev A, Shaik J, Morais da Fonseca D, Harrison OJ, Tamoutounour S, Byrd AL, et al. (2017). White adipose tissue is a reservoir for memory T cells and promotes protective memory responses to infection. Immunity 47, 1154–1168.e6.
- Herndler-Brandstetter D, Ishigame H, Shinnakasu R, Plajer V, Stecher C, Zhao J, Lietzenmayer M, Kroehling L, Takumi A, Kometani K, et al. (2018). KLRG1(+) effector CD8(+) T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716–729.e8.
- Huh JY, Park YJ, Ham M, and Kim JB (2014). Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol. Cells 37, 365–371.
- Huttunen R, and Syrjänen J (2013). Obesity and the risk and outcome of infection. Int. J. Obes 37, 333–340.
- Karlsson EA, Sheridan PA, and Beck MA (2010). Diet-induced obesity impairs the T cell memory response to influenza virus infection. J. Immunol 184, 3127–3133.
- Malide D (2008). Application of immunocytochemistry and immunofluorescence techniques to adipose tissue and cell cultures. Methods Mol. Biol 456, 285–297.
- Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rutishauser R, Cui W, Kleinstein SH, Craft J, and Kaech SM (2011). Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity 35, 633–646.
- Martínez J, Johnson CD, Sánchez-Payá J, de Madaria E, Robles-Díaz G, and Pérez-Mateo M (2006). Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis. Pancreatology 6, 206–209.
- Masopust D, Murali-Krishna K, and Ahmed R (2007). Quantitating the magnitude of the lymphocytic choriomeningitis virus-specific CD8 T-cell response: it is even bigger than we thought. J. Virol 81, 2002–2011.
- Milner JJ, and Beck MA (2012). The impact of obesity on the immune response to infection. Proc. Nutr. Soc 71, 298–306.
- Moraes-Vieira PM, Larocca RA, Bassi EJ, Peron JP, Andrade-Oliveira V, Wasinski F, Araujo R, Thornley T, Quintana FJ, Basso AS, et al. (2014). Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur. J. Immunol 44, 794–806.
- Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty CJ, Shiva SS, Durgampudi C, Karlsson JM, Lee K, Bae KT, et al. (2011). Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci. Transl. Med 3, 107ra110.
- Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med 15, 914–920.
- O’Brien KB, Vogel P, Duan S, Govorkova EA, Webby RJ, McCullers JA, and Schultz-Cherry S (2012). Impaired wound healing predisposes obese mice to severe influenza virus infection. J. Infect. Dis 205, 252–261.
- Papathanassoglou E, El-Haschimi K, Li XC, Matarese G, Strom T, and Mantzoros C (2006). Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J. Immunol 176, 7745–7752.
- Park J, Chang JH, Park SH, Lee HJ, Lim YS, Kim TH, Kim CW, and Han SW (2015). Interleukin-6 is associated with obesity, central fat distribution, and disease severity in patients with acute pancreatitis. Pancreatology 15, 59–63.
- Patel K, Trivedi RN, Durgampudi C, Noel P, Cline RA, DeLany JP, Navina S, and Singh VP (2015). Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. Am. J. Pathol 185, 808–819.
- Procaccini C, La Rocca C, Carbone F, De Rosa V, Galgani M, and Matarese G (2017). Leptin as immune mediator: Interaction between neuroendocrine and immune system. Dev. Comp. Immunol 66, 120–129.
- Rosen ED, and Spiegelman BM (2014). What we talk about when we talk about fat. Cell 156, 20–44.
- Schenkel JM, and Masopust D (2014). Tissue-resident memory T cells. Immunity 41, 886–897.
- Selin LK, Varga SM, Wong IC, and Welsh RM (1998). Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med 188, 1705–1715.
- Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG, Sammon AB, Holland LA, Weir S, Noah TL, and Beck MA (2012). Obesity is associated with impaired immune response to influenza vaccination in humans. Int. J. Obes 36, 1072–1077.
- Shin H, and Iwasaki A (2013). Tissue-resident memory T cells. Immunol. Rev 255, 165–181.
- Smith AG, Sheridan PA, Harp JB, and Beck MA (2007). Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J. Nutr 137, 1236–1243.
- Teixeira L, Marques RM, Ferreirinha P, Bezerra F, Melo J, Moreira J, Pinto A, Correia A, Ferreira PG, and Vilanova M (2016). Enrichment of IFN-g producing cells in different murine adipose tissue depots upon infection with an apicomplexan parasite. Sci. Rep 6, 23475.
- Tsatsanis C, Margioris AN, and Kontoyiannis DP (2010). Association between H1N1 infection severity and obesity-adiponectin as a potential etiologic factor. J. Infect. Dis 202, 459–460.
- Twig G, Geva N, Levine H, Derazne E, Goldberger N, Haklai Z, Leiba A, and Kark JD (2018). Body mass index and infectious disease mortality in midlife in a cohort of 2.3 million adolescents. Int. J. Obes. (Lond.) 42, 801–807.
- Welsh RM, Che JW, Brehm MA, and Selin LK (2010). Heterologous immunity between viruses. Immunol. Rev 235, 244–266.
- Yang HY, Joris I, Majno G, and Welsh RM (1985). Necrosis of adipose tissue induced by sequential infections with unrelated viruses. Am. J. Pathol 120, 173–177.
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