Abstract
Tertiary lymphoid structures (TLOs), also known as ectopic lymphoid structures, are associated with chronic infections and inflammatory diseases. Despite their association with pathology, these structures are actually a normal, albeit transient, component of the immune system and facilitate local immune responses that are meant to mitigate inflammation and resolve infection. Many of the mechanisms controlling the formation and function of tertiary lymphoid structures have been identified, in part by experimentally triggering their formation using defined stimuli under controlled conditions. Here, we introduce the experimental and pathological conditions in which tertiary lymphoid tissues are formed, describe the mechanisms linked to their formation, and discuss their functions in the context of both infection and inflammation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Cyster JG (2010) B cell follicles and antigen encounters of the third kind. Nat Immunol 11(11):989–996. https://doi.org/10.1038/ni.1946
Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7(4):344–353. https://doi.org/10.1038/ni1330
Dieu-Nosjean MC, Goc J, Giraldo NA et al (2014) Tertiary lymphoid structures in cancer and beyond. Trends Immunol 35(11):571–580. https://doi.org/10.1016/j.it.2014.09.006
Jones GW, Jones SA (2016) Ectopic lymphoid follicles: inducible centres for generating antigen-specific immune responses within tissues. Immunology 147(2):141–151. https://doi.org/10.1111/imm.12554
Randall TD, Mebius RE (2014) The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol 7(3):455–466. https://doi.org/10.1038/mi.2014.11
van de Pavert SA, Mebius RE (2010) New insights into the development of lymphoid tissues. Nat Rev Immunol 10(9):664–674. https://doi.org/10.1038/nri2832
Yin C, Mohanta S, Maffia P, Habenicht AJ (2017) Editorial: tertiary lymphoid organs (TLOs): powerhouses of disease immunity. Front Immunol 8:228. https://doi.org/10.3389/fimmu.2017.00228
Carragher DM, Rangel-Moreno J, Randall TD (2008) Ectopic lymphoid tissues and local immunity. Semin Immunol 20(1):26–42. https://doi.org/10.1016/j.smim.2007.12.004
Cruz-Migoni S, Caamano J (2016) Fat-associated lymphoid clusters in inflammation and immunity. Front Immunol 7:612. https://doi.org/10.3389/fimmu.2016.00612
Jones GW, Bombardieri M, Greenhill CJ et al (2015) Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J Exp Med 212(11):1793–1802. https://doi.org/10.1084/jem.20132307
Stahl FR, Heller K, Halle S et al (2013) Nodular inflammatory foci are sites of T cell priming and control of murine cytomegalovirus infection in the neonatal lung. PLoS Pathog 9(12):e1003828. https://doi.org/10.1371/journal.ppat.1003828
Pitzalis C, Jones GW, Bombardieri M, Jones SA (2014) Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol 14(7):447–462. https://doi.org/10.1038/nri3700
Moyron-Quiroz JE, Rangel-Moreno J, Kusser K et al (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10(9):927–934. https://doi.org/10.1038/nm1091
van de Pavert SA, Olivier BJ, Goverse G et al (2009) Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat Immunol 10(11):1193–1199. https://doi.org/10.1038/ni.1789
Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M et al (2011) The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol 12(7):639–646. https://doi.org/10.1038/ni.2053
Lochner M, Ohnmacht C, Presley L et al (2011) Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J Exp Med 208(1):125–134. https://doi.org/10.1084/jem.20100052
Cherrier M, Sawa S, Eberl G (2012) Notch, Id2, and RORgammat sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J Exp Med 209(4):729–740. https://doi.org/10.1084/jem.20111594
Kuroda E, Ozasa K, Temizoz B et al (2016) Inhaled fine particles induce alveolar macrophage death and interleukin-1alpha release to promote inducible bronchus-associated lymphoid tissue formation. Immunity 45(6):1299–1310. https://doi.org/10.1016/j.immuni.2016.11.010
Goya S, Matsuoka H, Mori M et al (2003) Sustained interleukin-6 signalling leads to the development of lymphoid organ-like structures in the lung. J Pathol 200(1):82–87. https://doi.org/10.1002/path.1321
Barone F, Nayar S, Campos J et al (2015) IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc Natl Acad Sci U S A 112(35):11,024–11,029. https://doi.org/10.1073/pnas.1503315112
Wengner AM, Hopken UE, Petrow PK et al (2007) CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum 56(10):3271–3283. https://doi.org/10.1002/art.22939
Thurlings RM, Wijbrandts CA, Mebius RE et al (2008) Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype. Arthritis Rheum 58(6):1582–1589. https://doi.org/10.1002/art.23505
Takemura S, Braun A, Crowson C et al (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167(2):1072–1080
Shi K, Hayashida K, Kaneko M et al (2001) Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol 166(1):650–655
Humby F, Bombardieri M, Manzo A et al (2009) Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med 6(1):e1. https://doi.org/10.1371/journal.pmed.0060001
Holdgate N, St Clair EW (2016) Recent advances in primary Sjogren's syndrome. F1000Res 5. https://doi.org/10.12688/f1000research.8352.1
Fava RA, Kennedy SM, Wood SG et al (2011) Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren's syndrome. Arthritis Res Ther 13(6):R182. https://doi.org/10.1186/ar3507
Bombardieri M, Barone F, Lucchesi D et al (2012) Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice. J Immunol 189(7):3767–3776. https://doi.org/10.4049/jimmunol.1201216
Serafini B, Rosicarelli B, Magliozzi R et al (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14(2):164–174
Pikor NB, Prat A, Bar-Or A, Gommerman JL (2015) Meningeal tertiary lymphoid tissues and multiple sclerosis: a gathering place for diverse types of immune cells during CNS autoimmunity. Front Immunol 6:657. https://doi.org/10.3389/fimmu.2015.00657
Pikor NB, Astarita JL, Summers-Deluca L et al (2015) Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 43(6):1160–1173. https://doi.org/10.1016/j.immuni.2015.11.010
Peters A, Pitcher LA, Sullivan JM et al (2011) Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35(6):986–996. https://doi.org/10.1016/j.immuni.2011.10.015
Mitsdoerffer M, Peters A (2016) Tertiary lymphoid organs in central nervous system autoimmunity. Front Immunol 7:451. https://doi.org/10.3389/fimmu.2016.00451
Magliozzi R, Columba-Cabezas S, Serafini B, Aloisi F (2004) Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 148(1-2):11–23. https://doi.org/10.1016/j.jneuroim.2003.10.056
Columba-Cabezas S, Griguoli M, Rosicarelli B et al (2006) Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin beta receptor-Ig fusion protein. J Neuroimmunol 179(1-2):76–86. https://doi.org/10.1016/j.jneuroim.2006.06.015
Hsieh C, Chang A, Brandt D et al (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63(6):865–874. https://doi.org/10.1002/acr.20441
Ludewig B, Odermatt B, Landmann S et al (1998) Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J Exp Med 188(8):1493–1501
Henry RA, Kendall PL (2010) CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice. J Immunol 185(3):1460–1465. https://doi.org/10.4049/jimmunol.0903710
Astorri E, Bombardieri M, Gabba S et al (2010) Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. J Immunol 185(6):3359–3368. https://doi.org/10.4049/jimmunol.1001836
Zhang X, Liu S, Chang T et al (2016) Intrathymic Tfh/B cells interaction leads to ectopic GCs formation and anti-AChR antibody production: central role in triggering MG occurrence. Mol Neurobiol 53(1):120–131. https://doi.org/10.1007/s12035-014-8985-1
Hill ME, Shiono H, Newsom-Davis J, Willcox N (2008) The myasthenia gravis thymus: a rare source of human autoantibody-secreting plasma cells for testing potential therapeutics. J Neuroimmunol 201-202:50–56. https://doi.org/10.1016/j.jneuroim.2008.06.027
Pei G, Zeng R, Han M et al (2014) Renal interstitial infiltration and tertiary lymphoid organ neogenesis in IgA nephropathy. Clin J Am Soc Nephrol 9(2):255–264. https://doi.org/10.2215/CJN.01150113
Magliozzi R, Howell O, Vora A et al (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130(Pt 4):1089–1104. https://doi.org/10.1093/brain/awm038
Chang A, Henderson SG, Brandt D et al (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186(3):1849–1860. https://doi.org/10.4049/jimmunol.1001983
Rangel-Moreno J, Hartson L, Navarro C et al (2006) Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest 116(12):3183–3194. https://doi.org/10.1172/JCI28756
Corsiero E, Bombardieri M, Carlotti E et al (2016) Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs. Ann Rheum Dis 75(10):1866–1875. https://doi.org/10.1136/annrheumdis-2015-208356
Scheel T, Gursche A, Zacher J et al (2011) V-region gene analysis of locally defined synovial B and plasma cells reveals selected B cell expansion and accumulation of plasma cell clones in rheumatoid arthritis. Arthritis Rheum 63(1):63–72. https://doi.org/10.1002/art.27767
Kim HJ, Berek C (2000) B cells in rheumatoid arthritis. Arthritis Res 2(2):126–131. https://doi.org/10.1186/ar77
Salomonsson S, Jonsson MV, Skarstein K et al (2003) Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum 48(11):3187–3201. https://doi.org/10.1002/art.11311
Zhang Z, Kyttaris VC, Tsokos GC (2009) The role of IL-23/IL-17 axis in lupus nephritis. J Immunol 183(5):3160–3169. https://doi.org/10.4049/jimmunol.0900385
Pisitkun P, Ha HL, Wang H et al (2012) Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis. Immunity 37(6):1104–1115. https://doi.org/10.1016/j.immuni.2012.08.014
Hirota K, Yoshitomi H, Hashimoto M et al (2007) Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 204(12):2803–2812. https://doi.org/10.1084/jem.20071397
Genovese MC, Durez P, Richards HB et al (2014) One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 41(3):414–421. https://doi.org/10.3899/jrheum.130637
Crispin JC, Oukka M, Bayliss G et al (2008) Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol 181(12):8761–8766
Nistala K, Adams S, Cambrook H et al (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A 107(33):14751–14756. https://doi.org/10.1073/pnas.1003852107
Harbour SN, Maynard CL, Zindl CL et al (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112(22):7061–7066. https://doi.org/10.1073/pnas.1415675112
Fleige H, Ravens S, Moschovakis GL et al (2014) IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. J Exp Med 211(4):643–651. https://doi.org/10.1084/jem.20131737
Eddens T, Elsegeiny W, Garcia-Hernadez ML et al (2017) Pneumocystis-driven inducible bronchus-associated lymphoid tissue formation requires Th2 and Th17 immunity. Cell Rep 18(13):3078–3090. https://doi.org/10.1016/j.celrep.2017.03.016
Rehal S, von der Weid PY (2017) TNFDeltaARE mice display abnormal lymphatics and develop tertiary lymphoid organs in the mesentery. Am J Pathol 187(4):798–807. https://doi.org/10.1016/j.ajpath.2016.12.007
Lee Y, Chin RK, Christiansen P et al (2006) Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure. Immunity 25(3):499–509. https://doi.org/10.1016/j.immuni.2006.06.016
Song HW, Yang C, Liu W et al (2017) Interleukin-17A plays the same role on mice acute lung injury respectively induced by lipopolysaccharide and paraquat. Inflammation 40:1509–1519. https://doi.org/10.1007/s10753-017-0592-7
Foo SY, Zhang V, Lalwani A et al (2015) Regulatory T cells prevent inducible BALT formation by dampening neutrophilic inflammation. J Immunol 194(9):4567–4576. https://doi.org/10.4049/jimmunol.1400909
Mohr E, Serre K, Manz RA et al (2009) Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol 182(4):2113–2123. https://doi.org/10.4049/jimmunol.0802771
Solleti SK, Srisuma S, Bhattacharya S et al (2016) Serpine2 deficiency results in lung lymphocyte accumulation and bronchus-associated lymphoid tissue formation. FASEB J 30(7):2615–2626. https://doi.org/10.1096/fj.201500159R
Picarella DE, Kratz A, Li CB et al (1993) Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol 150(9):4136–4150
Picarella DE, Kratz A, Li CB et al (1992) Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. Proc Natl Acad Sci U S A 89(21):10036–10040
Flavell RA, Kratz A, Ruddle NH (1996) The contribution of insulitis to diabetes development in tumor necrosis factor transgenic mice. Curr Top Microbiol Immunol 206:33–50
Penaranda C, Tang Q, Ruddle NH, Bluestone JA (2010) Prevention of diabetes by FTY720-mediated stabilization of peri-islet tertiary lymphoid organs. Diabetes 59(6):1461–1468. https://doi.org/10.2337/db09-1129
Mounzer RH, Svendsen OS, Baluk P et al (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116(12):2173–2182. https://doi.org/10.1182/blood-2009-12-256065
Zhang Q, Lu Y, Proulx ST et al (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9(6):R118. https://doi.org/10.1186/ar2326
Ansel KM, Ngo VN, Hyman PL et al (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406(6793):309–314. https://doi.org/10.1038/35018581
Luther SA, Bidgol A, Hargreaves DC et al (2002) Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169(1):424–433
Cyster JG (1999) Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. J Exp Med 189(3):447–450
Marinkovic T, Garin A, Yokota Y et al (2006) Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J Clin Invest 116(10):2622–2632. https://doi.org/10.1172/JCI28993
Marchesi F, Martin AP, Thirunarayanan N et al (2009) CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol 2(6):486–494. https://doi.org/10.1038/mi.2009.113
Furtado GC, Pacer ME, Bongers G et al (2014) TNFalpha-dependent development of lymphoid tissue in the absence of RORgammat(+) lymphoid tissue inducer cells. Mucosal Immunol 7(3):602–614. https://doi.org/10.1038/mi.2013.79
Chen L, He Z, Slinger E et al (2015) IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology. Mucosal Immunol 8(2):390–402. https://doi.org/10.1038/mi.2014.77
Meier D, Bornmann C, Chappaz S et al (2007) Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26(5):643–654. https://doi.org/10.1016/j.immuni.2007.04.009
Baluk P, Adams A, Phillips K et al (2014) Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. Am J Pathol 184(5):1577–1592. https://doi.org/10.1016/j.ajpath.2014.01.021
Gaur S, Trayner E, Aish L, Weinstein R (2004) Bronchus-associated lymphoid tissue lymphoma arising in a patient with bronchiectasis and chronic Mycobacterium avium infection. Am J Hematol 77(1):22–25. https://doi.org/10.1002/ajh.20136
Khader SA, Guglani L, Rangel-Moreno J, Gopal R et al (2011) IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung. J Immunol 187(10):5402–5407. https://doi.org/10.4049/jimmunol.1101377
Kaushal D, Foreman TW, Gautam US et al (2015) Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis. Nat Commun 6:8533. https://doi.org/10.1038/ncomms9533
Kahnert A, Hopken UE, Stein M et al (2007) Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J Infect Dis 195(1):46–54. https://doi.org/10.1086/508894
GeurtsvanKessel CH, Willart MA, Bergen IM et al (2009) Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med 206(11):2339–2349. https://doi.org/10.1084/jem.20090410
Kocks JR, Adler H, Danzer H et al (2009) Chemokine receptor CCR7 contributes to a rapid and efficient clearance of lytic murine gamma-herpes virus 68 from the lung, whereas bronchus-associated lymphoid tissue harbors virus during latency. J Immunol 182(11):6861–6869. https://doi.org/10.4049/jimmunol.0801826
Takamura S, Yagi H, Hakata Y et al (2016) Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance. J Exp Med 213(13):3057–3073. https://doi.org/10.1084/jem.20160938
Nakayama M, Ozaki H, Itoh Y et al (2016) Vaccination against H9N2 avian influenza virus reduces bronchus-associated lymphoid tissue formation in cynomolgus macaques after intranasal virus challenge infection. Pathol Int 66(12):678–686. https://doi.org/10.1111/pin.12472
Slight SR, Rangel-Moreno J, Gopal R et al (2013) CXCR5(+) T helper cells mediate protective immunity against tuberculosis. J Clin Invest 123(2):712–726. https://doi.org/10.1172/JCI65728
Khader SA, Gaffen SL, Kolls JK (2009) Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol 2(5):403–411. https://doi.org/10.1038/mi.2009.100
Shen H, Gu J, Xiao H et al (2017) Selective destruction of interleukin 23-induced expansion of a major antigen-specific gammadelta T-cell subset in patients with tuberculosis. J Infect Dis 215(3):420–430. https://doi.org/10.1093/infdis/jiw511
Shen H, Chen ZW (2017) The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection. Cell Mol Immunol 15:216–225. https://doi.org/10.1038/cmi.2017.128
Quesniaux VF, Jacobs M, Allie N et al (2010) TNF in host resistance to tuberculosis infection. Curr Dir Autoimmun 11:157–179. https://doi.org/10.1159/000289204
Day TA, Koch M, Nouailles G et al (2010) Secondary lymphoid organs are dispensable for the development of T-cell-mediated immunity during tuberculosis. Eur J Immunol 40(6):1663–1673. https://doi.org/10.1002/eji.201040299
Allie N, Keeton R, Court N et al (2010) Limited role for lymphotoxin alpha in the host immune response to Mycobacterium tuberculosis. J Immunol 185(7):4292–4301. https://doi.org/10.4049/jimmunol.1000650
Hu D, Mohanta SK, Yin C et al (2015) Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin beta receptors. Immunity 42(6):1100–1115. https://doi.org/10.1016/j.immuni.2015.05.015
Fletcher AL, Lukacs-Kornek V, Reynoso ED et al (2010) Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med 207(4):689–697. https://doi.org/10.1084/jem.20092642
Cohen JN, Guidi CJ, Tewalt EF et al (2010) Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207(4):681–688. https://doi.org/10.1084/jem.20092465
Warren KJ, Iwami D, Harris DG et al (2014) Laminins affect T cell trafficking and allograft fate. J Clin Invest 124(5):2204–2218. https://doi.org/10.1172/JCI73683
Baptista AP, Roozendaal R, Reijmers RM et al (2014) Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. Elife 3. https://doi.org/10.7554/eLife.04433
Siegert S, Huang HY, Yang CY et al (2011) Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS One 6(11):e27618. https://doi.org/10.1371/journal.pone.0027618
Lukacs-Kornek V, Malhotra D, Fletcher AL et al (2011) Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 12(11):1096–1104. https://doi.org/10.1038/ni.2112
Khan O, Headley M, Gerard A et al (2011) Regulation of T cell priming by lymphoid stroma. PLoS One 6(11):e26138. https://doi.org/10.1371/journal.pone.0026138
Zinocker S, Vaage JT (2012) Rat mesenchymal stromal cells inhibit T cell proliferation but not cytokine production through inducible nitric oxide synthase. Front Immunol 3:62. https://doi.org/10.3389/fimmu.2012.00062
Matloubian M, Lo CG, Cinamon G et al (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427(6972):355–360. https://doi.org/10.1038/nature02284
Sawicka E, Zuany-Amorim C, Manlius C et al (2003) Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. J Immunol 171(11):6206–6214
Idzko M, Hammad H, van Nimwegen M et al (2006) Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 116(11):2935–2944. https://doi.org/10.1172/JCI28295
Kocks JR, Davalos-Misslitz AC, Hintzen G et al (2007) Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J Exp Med 204(4):723–734. https://doi.org/10.1084/jem.20061424
Brinkmann V, Billich A, Baumruker T et al (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9(11):883–897. https://doi.org/10.1038/nrd3248
Shin K, Kataru RP, Park HJ et al (2015) TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat Commun 6:6196. https://doi.org/10.1038/ncomms7196
Randolph GJ, Angeli V, Swartz MA (2005) Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5(8):617–628. https://doi.org/10.1038/nri1670
Loo CP, Nelson NA, Lane RS et al (2017) Lymphatic vessels balance viral dissemination and immune activation following cutaneous viral infection. Cell Rep 20(13):3176–3187. https://doi.org/10.1016/j.celrep.2017.09.006
Kataru RP, Lee YG, Koh GY (2014) Interactions of immune cells and lymphatic vessels. Adv Anat Embryol Cell Biol 214:107–118. https://doi.org/10.1007/978-3-7091-1646-3_9
Roozendaal R, Mebius RE (2011) Stromal cell-immune cell interactions. Annu Rev Immunol 29:23–43. https://doi.org/10.1146/annurev-immunol-031210-101357
Meza-Perez S, Randall TD (2017) Immunological functions of the omentum. Trends Immunol 38(7):526–536. https://doi.org/10.1016/j.it.2017.03.002
Benezech C, Luu NT, Walker JA et al (2015) Inflammation-induced formation of fat-associated lymphoid clusters. Nat Immunol 16(8):819–828. https://doi.org/10.1038/ni.3215
Wagnetz D, Sato M, Hirayama S et al (2012) Rejection of tracheal allograft by intrapulmonary lymphoid neogenesis in the absence of secondary lymphoid organs. Transplantation 93(12):1212–1220. https://doi.org/10.1097/TP.0b013e318250fbf5
Sautes-Fridman C, Fridman WH (2016) TLS in tumors: what lies within. Trends Immunol 37(1):1–2. https://doi.org/10.1016/j.it.2015.12.001
Nasr IW, Reel M, Oberbarnscheidt MH et al (2007) Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transplant 7(5):1071–1079. https://doi.org/10.1111/j.1600-6143.2007.01756.x
Gelman AE, Li W, Richardson SB et al (2009) Cutting edge: acute lung allograft rejection is independent of secondary lymphoid organs. J Immunol 182(7):3969–3973. https://doi.org/10.4049/jimmunol.0803514
Sicard A, Chen CC, Morelon E, Thaunat O (2016) Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection. Curr Opin Organ Transplant 21(4):368–374. https://doi.org/10.1097/MOT.0000000000000329
Li W, Bribriesco AC, Nava RG, Brescia AA et al (2012) Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis. Mucosal Immunol 5(5):544–554. https://doi.org/10.1038/mi.2012.30
Le Texier L, Thebault P, Lavault A et al (2011) Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. Am J Transplant 11(3):429–438. https://doi.org/10.1111/j.1600-6143.2010.03336.x
Legoux FP, Lim JB, Cauley AW et al (2015) CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43(5):896–908. https://doi.org/10.1016/j.immuni.2015.10.011
Hiraoka N, Ino Y, Yamazaki-Itoh R (2016) Tertiary lymphoid organs in cancer tissues. Front Immunol 7:244. https://doi.org/10.3389/fimmu.2016.00244
Dieu-Nosjean MC, Giraldo NA, Kaplon H et al (2016) Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev 271(1):260–275. https://doi.org/10.1111/imr.12405
Dieu-Nosjean MC, Antoine M, Danel C et al (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26(27):4410–4417. https://doi.org/10.1200/JCO.2007.15.0284
de Chaisemartin L, Goc J, Damotte D et al (2011) Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res 71(20):6391–6399. https://doi.org/10.1158/0008-5472.CAN-11-0952
Weinstein AM, Chen L, Brzana EA et al (2017) Tbet and IL-36gamma cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment. Oncoimmunology 6(6):e1322238. https://doi.org/10.1080/2162402X.2017.1322238
Hiraoka N, Ino Y, Yamazaki-Itoh R et al (2015) Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer 112(11):1782–1790. https://doi.org/10.1038/bjc.2015.145
Joshi NS, Akama-Garren EH, Lu Y et al (2015) Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43(3):579–590. https://doi.org/10.1016/j.immuni.2015.08.006
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Silva-Sanchez, A., Randall, T.D., Meza-Perez, S. (2018). Tertiary Lymphoid Structures Among the World of Noncanonical Ectopic Lymphoid Organizations. In: Dieu-Nosjean, MC. (eds) Tertiary Lymphoid Structures. Methods in Molecular Biology, vol 1845. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8709-2_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8709-2_1
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8708-5
Online ISBN: 978-1-4939-8709-2
eBook Packages: Springer Protocols