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Innate Lymphoid Cells: Their Contributions to Gastrointestinal Tissue Homeostasis and HIV/SIV Disease Pathology

  • Joseph C. Mudd
  • Jason M. BrenchleyEmail author
HIV Pathogenesis and Treatment (AL Landay and NS Utay, Section Editors)
  • 59 Downloads
Part of the following topical collections:
  1. Topical Collection on HIV Pathogenesis and Treatment

Abstract

Purpose of Review

The discovery of innate lymphoid cells (ILCs) over the past decade has reformed principles that were once thought to be exclusive to adaptive immunity. Here, we describe ILC nomenclature and function, and provide a survey of studies examining these cells in the context of HIV/SIV infections. Particular emphasis is placed on the ILC3 subset, important for proper functioning of the gastrointestinal tract barrier.

Recent Findings

Studies in both humans and nonhuman primates have found ILCs to be rapidly and durably depleted in untreated HIV/SIV infections. Their depletion is most likely due to a number of bystander effects induced by viral replication.

Summary

Given the number of associations observed between loss of ILCs and HIV-related GI damage, their impact on the GI tract is likely important. It may be informative to examine this subset in parallel with other immune cell types when assessing overall health of the GI tract in future studies.

Keywords

ILCs GI tissue HIV pathogenesis 

Notes

Funding Information

Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH.

Compliance with Ethical Standards

Disclaimer

The content of this publication does not necessarily reflect the views or policies of DHHS, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200(6):749–59.Google Scholar
  2. 2.
    Rodgers VD, Fassett R, Kagnoff MF. Abnormalities in intestinal mucosal T cells in homosexual populations including those with the lymphadenopathy syndrome and acquired immunodeficiency syndrome. Gastroenterology. 1986;90(3):552–8.Google Scholar
  3. 3.
    Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434(7037):1148–52.Google Scholar
  4. 4.
    Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.Google Scholar
  5. 5.
    Estes JD, Kityo C, Ssali F, Swainson L, Makamdop KN, Del Prete GQ, et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nat Med. 2017;23(11):1271–6.Google Scholar
  6. 6.
    Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest. 2011;121(3):998–1008.Google Scholar
  7. 7.
    Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119:51–83.Google Scholar
  8. 8.
    Klatt NR, Canary LA, Sun X, Vinton CL, Funderburg NT, Morcock DR, et al. Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. J Clin Invest. 2013;123(2):903–7.Google Scholar
  9. 9.
    Estes JD, Reilly C, Trubey CM, Fletcher CV, Cory TJ, Piatak M Jr, et al. Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy. J Infect Dis. 2015;211(5):744–54.Google Scholar
  10. 10.
    Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009;457(7230):722–5.Google Scholar
  11. 11.
    Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463(7280):540–4.Google Scholar
  12. 12.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–70.Google Scholar
  13. 13.
    Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker JE, et al. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature. 2010;464(7293):1362–6.Google Scholar
  14. 14.
    Hazenberg MD, Spits H. Human innate lymphoid cells. Blood. 2014;124(5):700–9.Google Scholar
  15. 15.
    Martin CE, Spasova DS, Frimpong-Boateng K, Kim HO, Lee M, Kim KS, et al. Interleukin-7 availability is maintained by a hematopoietic cytokine sink comprising innate lymphoid cells and T cells. Immunity. 2017;47(1):171–82 e4.Google Scholar
  16. 16.
    Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013;14(3):221–9.Google Scholar
  17. 17.
    Gasteiger G, Fan X, Dikiy S, Lee SY, Rudensky AY. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015;350(6263):981–5.Google Scholar
  18. 18.
    Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med. 2014;211(3):563–77.Google Scholar
  19. 19.
    Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012;36(1):55–67.Google Scholar
  20. 20.
    Beziat V, Duffy D, Quoc SN, Le Garff-Tavernier M, Decocq J, Combadiere B, et al. CD56brightCD16+ NK cells: a functional intermediate stage of NK cell differentiation. J Immunol. 2011;186(12):6753–61.Google Scholar
  21. 21.
    •• Simoni Y, Fehlings M, Kloverpris HN, McGovern N, Koo SL, Loh CY, et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity. 2018;48(5):1060 This provides a multi-dimensional phenotypic analysis of ILCs across multiple human tissues. Likely the most comrehensive chacterization to date in humans. Google Scholar
  22. 22.
    •• Mudd JC, Busman-Sahay K, DiNapoli SR, Lai S, Sheik V, Lisco A, et al. Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells. Nat Commun. 2018;9(1):3967 This study sheds important light on potential mechanisms of SIV/HIV-associated ILC depletion. Google Scholar
  23. 23.
    Bjorklund AK, Forkel M, Picelli S, Konya V, Theorell J, Friberg D, et al. The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016;17(4):451–60.Google Scholar
  24. 24.
    Roan F, Stoklasek TA, Whalen E, Molitor JA, Bluestone JA, Buckner JH, et al. CD4+ group 1 innate lymphoid cells (ILC) form a functionally distinct ILC subset that is increased in systemic sclerosis. J Immunol. 2016;196(5):2051–62.Google Scholar
  25. 25.
    Zhao J, Cheng L, Wang H, Yu H, Tu B, Fu Q, et al. Infection and depletion of CD4+ group-1 innate lymphoid cells by HIV-1 via type-I interferon pathway. PLoS Pathog. 2018;14(1):e1006819.Google Scholar
  26. 26.
    Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, et al. Systemic human ILC precursors provide a substrate for tissue ILC differentiation. Cell. 2017;168(6):1086–100 e10.Google Scholar
  27. 27.
    Scoville SD, Mundy-Bosse BL, Zhang MH, Chen L, Zhang X, Keller KA, et al. A progenitor cell expressing transcription factor RORgammat generates all human innate lymphoid cell subsets. Immunity. 2016;44(5):1140–50.Google Scholar
  28. 28.
    Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013;5(170):170ra16.Google Scholar
  29. 29.
    Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 2012;37(4):634–48.Google Scholar
  30. 30.
    Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12(11):1055–62.Google Scholar
  31. 31.
    Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM, Golebski K, et al. IL-1beta, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol. 2016;17(6):636–45.Google Scholar
  32. 32.
    Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M, Yu L, et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat Immunol. 2016;17(6):626–35.Google Scholar
  33. 33.
    Ohne Y, Silver JS, Thompson-Snipes L, Collet MA, Blanck JP, Cantarel BL, et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat Immunol. 2016;17(6):646–55.Google Scholar
  34. 34.
    Lim AI, Menegatti S, Bustamante J, Le Bourhis L, Allez M, Rogge L, et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J Exp Med. 2016;213(4):569–83.Google Scholar
  35. 35.
    Oliphant CJ, Hwang YY, Walker JA, Salimi M, Wong SH, Brewer JM, et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity. 2014;41(2):283–95.Google Scholar
  36. 36.
    Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2015;519(7542):242–6.Google Scholar
  37. 37.
    Licona-Limon P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol. 2013;14(6):536–42.Google Scholar
  38. 38.
    Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013;502(7470):245–8.Google Scholar
  39. 39.
    Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17(7):765–74.Google Scholar
  40. 40.
    Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174(5):1054–66.Google Scholar
  41. 41.
    Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, Chasson L, et al. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol. 2009;10(1):75–82.Google Scholar
  42. 42.
    Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10(1):66–74.Google Scholar
  43. 43.
    Glatzer T, Killig M, Meisig J, Ommert I, Luetke-Eversloh M, Babic M, et al. RORgammat(+) innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity. 2013;38(6):1223–35.Google Scholar
  44. 44.
    Cella M, Otero K, Colonna M. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc Natl Acad Sci U S A. 2010;107(24):10961–6.Google Scholar
  45. 45.
    Bernink JH, Krabbendam L, Germar K, de Jong E, Gronke K, Kofoed-Nielsen M, et al. Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity. 2015;43(1):146–60.Google Scholar
  46. 46.
    •• Kramer B, Goeser F, Lutz P, Glassner A, Boesecke C, Schwarze-Zander C, et al. Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy. PLoS Pathog. 2017;13(5):e1006373 Likely the most comprehensive assessment of ILC3s in human intestinal tissues. Google Scholar
  47. 47.
    Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012;336(6086):1321–5.Google Scholar
  48. 48.
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118(2):534–44.Google Scholar
  49. 49.
    Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282–9.Google Scholar
  50. 50.
    Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000;118(6):1001–11.Google Scholar
  51. 51.
    Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14(3):275–81.Google Scholar
  52. 52.
    Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity. 2008;29(6):958–70.Google Scholar
  53. 53.
    Crellin NK, Trifari S, Kaplan CD, Satoh-Takayama N, Di Santo JP, Spits H. Regulation of cytokine secretion in human CD127(+) LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity. 2010;33(5):752–64.Google Scholar
  54. 54.
    Longman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, et al. CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med. 2014;211(8):1571–83.Google Scholar
  55. 55.
    Mao K, Baptista AP, Tamoutounour S, Zhuang L, Bouladoux N, Martins AJ, et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature. 2018;554(7691):255–9.Google Scholar
  56. 56.
    Kim SH, Cho BH, Kiyono H, Jang YS. Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer’s patches. Sci Rep. 2017;7(1):3980.Google Scholar
  57. 57.
    Perdew GH, Babbs CF. Production of Ah receptor ligands in rat fecal suspensions containing tryptophan or indole-3-carbinol. Nutr Cancer. 1991;16(3–4):209–18.Google Scholar
  58. 58.
    Zelante T, Iannitti RG, Fallarino F, Gargaro M, De Luca A, Moretti S, et al. Tryptophan feeding of the IDO1-AhR axis in host-microbial symbiosis. Front Immunol. 2014;5:640.Google Scholar
  59. 59.
    Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K, Amin SG, et al. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep. 2015;5:12689.Google Scholar
  60. 60.
    Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011;334(6062):1561–5.Google Scholar
  61. 61.
    Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol. 2011;13(2):144–51.Google Scholar
  62. 62.
    Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012;36(1):92–104.Google Scholar
  63. 63.
    Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011;208(6):1127–33.Google Scholar
  64. 64.
    Eken A, Singh AK, Treuting PM, Oukka M. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 2014;7(1):143–54.Google Scholar
  65. 65.
    Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464(7293):1371–5.Google Scholar
  66. 66.
    Rankin LC, Girard-Madoux MJ, Seillet C, Mielke LA, Kerdiles Y, Fenis A, et al. Complementarity and redundancy of IL-22-producing innate lymphoid cells. Nat Immunol. 2016;17(2):179–86.Google Scholar
  67. 67.
    Song C, Lee JS, Gilfillan S, Robinette ML, Newberry RD, Stappenbeck TS, et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J Exp Med. 2015;212(11):1869–82.Google Scholar
  68. 68.
    Vely F, Barlogis V, Vallentin B, Neven B, Piperoglou C, Ebbo M, et al. Evidence of innate lymphoid cell redundancy in humans. Nat Immunol. 2016;17(11):1291–9.Google Scholar
  69. 69.
    Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113–7.Google Scholar
  70. 70.
    Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5(193):193ra91.Google Scholar
  71. 71.
    Mudd JC, Brenchley JM. Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J Infect Dis. 2016;214(Suppl 2):S58–66.Google Scholar
  72. 72.
    Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008;112(7):2826–35.Google Scholar
  73. 73.
    Nilssen DE, Muller F, Oktedalen O, Froland SS, Fausa O, Halstensen TS, et al. Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune state and survival time in AIDS. J Virol. 1996;70(6):3545–50.Google Scholar
  74. 74.
    Cosgrove C, Ussher JE, Rauch A, Gartner K, Kurioka A, Huhn MH, et al. Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection. Blood. 2013;121(6):951–61.Google Scholar
  75. 75.
    Schuetz A, Deleage C, Sereti I, Rerknimitr R, Phanuphak N, Phuang-Ngern Y, et al. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog. 2014;10(12):e1004543.Google Scholar
  76. 76.
    Zhang Z, Cheng L, Zhao J, Li G, Zhang L, Chen W, et al. Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion. J Clin Invest. 2015;125(9):3692–703.Google Scholar
  77. 77.
    •• Kloverpris HN, Kazer SW, Mjosberg J, Mabuka JM, Wellmann A, Ndhlovu Z, et al. Innate lymphoid cells are depleted irreversibly during acute HIV-1 infection in the absence of viral suppression. Immunity. 2016;44(2):391–405 The most comprehensive characterization of blood ILCs in HIV-1 disease course. Google Scholar
  78. 78.
    Fernandes SM, Pires AR, Ferreira C, Foxall RB, Rino J, Santos C, et al. Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals. J Infect Dis. 2014;210(4):630–40.Google Scholar
  79. 79.
    Dillon SM, Castleman MJ, Frank DN, Austin GL, Gianella S, Cogswell AC, et al. Brief report: inflammatory colonic innate lymphoid cells are increased during untreated HIV-1 infection and associated with markers of gut dysbiosis and mucosal immune activation. J Acquir Immune Defic Syndr. 2017;76(4):431–7.Google Scholar
  80. 80.
    Steinert EM, Schenkel JM, Fraser KA, Beura LK, Manlove LS, Igyarto BZ, et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell. 2015;161(4):737–49.Google Scholar
  81. 81.
    Estes JD, Wong SW, Brenchley JM. Nonhuman primate models of human viral infections. Nat Rev Immunol. 2018;18(6):390–404.Google Scholar
  82. 82.
    Klatt NR, Estes JD, Sun X, Ortiz AM, Barber JS, Harris LD, et al. Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection. Mucosal Immunol. 2012;5(6):646–57.Google Scholar
  83. 83.
    Xu H, Wang X, Liu DX, Moroney-Rasmussen T, Lackner AA, Veazey RS. IL-17-producing innate lymphoid cells are restricted to mucosal tissues and are depleted in SIV-infected macaques. Mucosal Immunol. 2012;5(6):658–69.Google Scholar
  84. 84.
    •• Reeves RK, Rajakumar PA, Evans TI, Connole M, Gillis J, Wong FE, et al. Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection. Blood. 2011, 12, 3321;118:–30 The first characterization of the dynamics of colon NKp44+ ILC3s in SIV infection. Google Scholar
  85. 85.
    Li H, Richert-Spuhler LE, Evans TI, Gillis J, Connole M, Estes JD, et al. Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. PLoS Pathog. 2014;10(12):e1004551.Google Scholar
  86. 86.
    Liyanage NP, Gordon SN, Doster MN, Pegu P, Vaccari M, Shukur N, et al. Antiretroviral therapy partly reverses the systemic and mucosal distribution of NK cell subsets that is altered by SIVmac(2)(5)(1) infection of macaques. Virology. 2014;450–451:359–68.Google Scholar
  87. 87.
    Kim CJ, Nazli A, Rojas OL, Chege D, Alidina Z, Huibner S, et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 2012;5(6):670–80.Google Scholar
  88. 88.
    Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol. 2009;83(8):3719–33.Google Scholar
  89. 89.
    Bosinger SE, Li Q, Gordon SN, Klatt NR, Duan L, Xu L, et al. Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest. 2009;119(12):3556–72.Google Scholar
  90. 90.
    Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2(32):32ra6.Google Scholar
  91. 91.
    Fuchs D, Moller AA, Reibnegger G, Werner ER, Werner-Felmayer G, Dierich MP, et al. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunol Lett. 1991;28(3):207–11.Google Scholar
  92. 92.
    Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;183(4):2475–83.Google Scholar
  93. 93.
    Wuest SC, Edwan JH, Martin JF, Han S, Perry JS, Cartagena CM, et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med. 2011;17(5):604–9.Google Scholar
  94. 94.
    Perry JS, Han S, Xu Q, Herman ML, Kennedy LB, Csako G, et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci Transl Med. 2012;4(145):145ra06.Google Scholar
  95. 95.
    Gaardbo JC, Hartling HJ, Thorsteinsson K, Ullum H, Nielsen SD. CD3+CD8+CD161high Tc17 cells are depleted in HIV-infection. AIDS. 2013;27(4):659–62.Google Scholar
  96. 96.
    Thiebaut R, Jarne A, Routy JP, Sereti I, Fischl M, Ive P, et al. Repeated cycles of recombinant human interleukin 7 in HIV-infected patients with low CD4 T-cell reconstitution on antiretroviral therapy: results of 2 phase II multicenter studies. Clin Infect Dis. 2016;62(9):1178–85.Google Scholar
  97. 97.
    Micci L, Ryan ES, Fromentin R, Bosinger SE, Harper JL, He T, et al. Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques. J Clin Invest. 2015;125(12):4497–513.Google Scholar
  98. 98.
    Vaccari M, Gordon SN, Fourati S, Schifanella L, Liyanage NP, Cameron M, et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat Med. 2016;22(7):762–70.Google Scholar

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© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Barrier Immunity Section, Lab of Viral DiseasesNational Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

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