Orchestrated leukocyte recruitment to immune-privileged sites: Absolute barriers versus educational gates

Nature Reviews Immunology

Volumn 13, Issue 3, 2013, Pages 206-218

  Shechter, Ravid ^a   London, Anat ^a   Schwartz, Michal ^a  

^a WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; HUMAN; IMMUNOREGULATION; INFLAMMATION; LEUKOCYTE; PRIORITY JOURNAL; REVIEW;

ANIMALS; BLOOD-AQUEOUS BARRIER; BLOOD-BRAIN BARRIER; BLOOD-RETINAL BARRIER; BLOOD-TESTIS BARRIER; CELL FUSION; CHEMOTAXIS, LEUKOCYTE; CHIMERISM; EPITHELIAL CELLS; EPITHELIUM; FEMALE; HUMANS; IMMUNE TOLERANCE; IMMUNOLOGIC SURVEILLANCE; INFLAMMATION; MALE; MATERNAL-FETAL EXCHANGE; MODELS, IMMUNOLOGICAL; NEUTROPHIL INFILTRATION; ORGAN SPECIFICITY; PREGNANCY; TIGHT JUNCTIONS; TRANSENDOTHELIAL AND TRANSEPITHELIAL MIGRATION;

EID: 84875414225     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3391     Document Type: Review

References (141)

1. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678-689 (2007). (Pubitemid 47327397)
2. Huber, D., Balda, M. S. & Matter, K. Occludin modulates transepithelial migration of neutrophils. J. Biol. Chem. 275, 5773-5778 (2000). (Pubitemid 30115221)
3. Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nature Rev. Immunol. 12, 623-635 (2012).
4. Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nature Rev. Immunol. 3, 879-889 (2003). (Pubitemid 37411717)
5. Naito, M. et al. The presence of intra-tubular lymphocytes in normal testis of the mouse. Okajimas Folia Anat. Jpn 85, 91-96 (2008).
6. Goyal, H. O. & Williams, C. S. The rete testis of the goat, a morphological study. Acta Anat. (Basel) 130, 151-157 (1987).
7. Nelson, J. L. The otherness of self: microchimerism in health and disease. Trends Immunol. 33, 421-427 (2012).
8. Takashima, S. et al. Rac mediates mouse spermatogonial stem cell homing to germline niches by regulating transmigration through the blood-testis barrier. Cell Stem Cell 9, 463-475 (2011).
9. Wang, C. Q. & Cheng, C. Y. A seamless trespass: germ cell migration across the seminiferous epithelium during spermatogenesis. J. Cell Biol. 178, 549-556 (2007). (Pubitemid 47267267)
10. Engelhardt, B. & Ransohoff, R. M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579-589 (2012).
11. Alvarez, J. I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727-1731 (2011).
12. Sonobe, Y. et al. Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cε-dependent manner. J. Biol. Chem. 284, 31834-31842 (2009).
13. Cruz-Orengo, L. et al. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J. Exp. Med. 208, 327-339 (2011).
14. McCandless, E. E., Wang, Q., Woerner, B. M., Harper, J. M. & Klein, R. S. CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J. Immunol. 177, 8053-8064 (2006). (Pubitemid 44846323)
15. Alt, C., Laschinger, M. & Engelhardt, B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur. J. Immunol. 32, 2133-2144 (2002). (Pubitemid 34965876)
16. Galea, I. et al. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J. Exp. Med. 204, 2023-2030 (2007). (Pubitemid 47360864)
17. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Med. 11, 328-334 (2005). (Pubitemid 40460562)
18. Ifergan, I. et al. The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 131, 785-799 (2008). (Pubitemid 351294709)
19. Seguin, R., Biernacki, K., Rotondo, R. L., Prat, A. & Antel, J. P. Regulation and functional effects of monocyte migration across human brain-derived endothelial cells. J. Neuropathol. Exp. Neurol. 62, 412-419 (2003). (Pubitemid 36403041)
20. Agrawal, S. et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J. Exp. Med. 203, 1007-1019 (2006).
21. Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity (in the press).
22. Provencio, J. J., Kivisakk, P., Tucky, B. H., Luciano, M. G. & Ransohoff, R. M. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J. Neuroimmunol. 163, 179-184 (2005). (Pubitemid 40692961)
23. Baruch, K. et al. CNS-specific immunity at the choroid plexus shifts towards destructive Th2-inflammation in brain aging. Proc. Natl Acad. Sci. USA 18 Jan 2013 (doi:10.1073/pnas.1211270110).
24. Kivisakk, P. et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl Acad. Sci. USA 100, 8389-8394 (2003). (Pubitemid 36842555)
25. Buonamici, S. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000-1004 (2009).
26. Taylor, A. W. & Streilein, J. W. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation 3, 112-118 (1996). (Pubitemid 26373866)
27. Trabold, B., Rothoerl, R., Wittmann, S., Woertgen, C. & Frohlich, D. Cerebrospinal fluid and neutrophil respiratory burst after subarachnoid hemorrhage. Neuroimmunomodulation 12, 152-156 (2005). (Pubitemid 40868675)
28. Gordon, L. B., Nolan, S. C., Ksander, B. R., Knopf, P. M. & Harling-Berg, C. J. Normal cerebrospinal fluid suppresses the in vitro development of cytotoxic T cells: role of the brain microenvironment in CNS immune regulation. J. Neuroimmunol. 88, 77-84 (1998). (Pubitemid 28342906)
29. De Rotte, A. A., Verhoef, J., Andringa-Bakker, E. A. & Van Wimersma Greidanus, T. B. Characterization of the α-MSH-like immunoreactivity in blood and cerebrospinal fluid of the rat. Acta Endocrinol. 111, 440-444 (1986). (Pubitemid 16086307)
30. Suzuki, H. et al. Pituitary protein 7B2-like immunoreactivity in cerebrospinal fluid: comparison with other neuropeptides. J. Lab. Clin. Med. 113, 743-748 (1989). (Pubitemid 19151684)
31. Pentreath, V. W., Rees, K., Owolabi, O. A., Philip, K. A. & Doua, F. The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Trans. R. Soc. Trop. Med. Hyg. 84, 795-799 (1990).
32. Tarkowski, E., Liljeroth, A. M., Nilsson, A., Minthon, L. & Blennow, K. Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 12, 314-317 (2001). (Pubitemid 32656663)
33. Haginoya, K. et al. Reduced levels of interleukin-1 receptor antagonist in the cerebrospinal fluid in patients with West syndrome. Epilepsy Res. 85, 314-317 (2009).
34. Mueller, A. M., Pedre, X., Killian, S., David, M. & Steinbrecher, A. The Decoy Receptor 3 (DcR3, TNFRSF6B) suppresses Th17 immune responses and is abundant in human cerebrospinal fluid. J. Neuroimmunol. 209, 57-64 (2009).
35. Pan, Y. et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387, 611-617 (1997). (Pubitemid 27248766)
36. Mills, J. H. et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 9325-9330 (2008).
37. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257-1265 (2007). (Pubitemid 46919862)
38. Mills, J. H., Kim, D. G., Krenz, A., Chen, J. F. & Bynoe, M. S. A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J. Immunol. 188, 5713-5722 (2012).
39. Fujiwara, M. et al. Indoleamine 2,3-dioxygenase. Formation of L-kynurenine from L-tryptophan in cultured rabbit fineal gland. J. Biol. Chem. 253, 6081-6085 (1978). (Pubitemid 9014249)
40. Yamamoto, M., Drager, U. C., Ong, D. E. & McCaffery, P. Retinoid-binding proteins in the cerebellum and choroid plexus and their relationship to regionalized retinoic acid synthesis and degradation. Eur. J. Biochem. 257, 344-350 (1998). (Pubitemid 28489479)
41. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514-523 (2009).
42. Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877-2886 (2005). (Pubitemid 40446282)
43. Schulz, M. & Engelhardt, B. The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res. 266, 8 (2005).
44. Schmitt, C., Strazielle, N. & Ghersi-Egea, J. F. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain. J. Neuroinflamm. 966, 187 (2012).
45. Alvarez, J. I. & Teale, J. M. Differential changes in junctional complex proteins suggest the ependymal lining as the main source of leukocyte infiltration into ventricles in murine neurocysticercosis. J. Neuroimmunol. 187, 102-113 (2007). (Pubitemid 47001551)
46. Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863-4870 (2010).
47. Marvar, P. J. et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ. Res. 107, 263-270 (2010).
48. Carrithers, M. D., Visintin, I., Kang, S. J. & Janeway, C. A. Jr. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 123, 1092-1101 (2000). (Pubitemid 30312102)
49. Piccio, L. et al. Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors. J. Immunol. 168, 1940-1949 (2002). (Pubitemid 34135797)
50. Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067-1080 (2010).
51. Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191-195 (2009).
52. Bartholomaus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94-98 (2009).
53. Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature Neurosci. 14, 1142-1149 (2011).
54. Kivisakk, P. et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol. 65, 457-469 (2009).
55. Wieseler-Frank, J. et al. A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus. Brain Behav. Immun. 21, 711-718 (2007). (Pubitemid 46829767)
56. Kaur, C., Foulds, W. S. & Ling, E. A. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res. 27, 622-647 (2008).
57. Luna, J. D. et al. Blood-retinal barrier (BRB) breakdown in experimental autoimmune uveoretinitis: comparison with vascular endothelial growth factor, tumor necrosis factor α, and interleukin-1β-mediated breakdown. J. Neurosci. Res. 49, 268-280 (1997). (Pubitemid 27344187)
58. Kerr, E. C., Copland, D. A., Dick, A. D. & Nicholson, L. B. The dynamics of leukocyte infiltration in experimental autoimmune uveoretinitis. Prog. Retin. Eye Res. 27, 527-535 (2008).
59. Luger, D. et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799-810 (2008). (Pubitemid 351549879)
60. Parnaby-Price, A. et al. Leukocyte trafficking in experimental autoimmune uveitis in vivo. J. Leukoc. Biol. 64, 434-440 (1998). (Pubitemid 28455388)
61. Joly, S. et al. Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions. Am. J. Pathol. 174, 2310-2323 (2009).
62. Sugita, S., Futagami, Y., Smith, S. B., Naggar, H. & Mochizuki, M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor β. Exp. Eye Res. 83, 1459-1471 (2006). (Pubitemid 44648106)
63. Sugita, S. Role of ocular pigment epithelial cells in immune privilege. Arch. Immunol. Ther. Exp. (Warsz) 57, 263-268 (2009).
64. Fang, Y., Yu, S., Ellis, J. S., Sharav, T. & Braley-Mullen, H. Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. J. Leukoc. Biol. 87, 1019-1028 (2010).
65. Ishida, K., Panjwani, N., Cao, Z. & Streilein, J. W. Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms. Ocul. Immunol. Inflamm. 11, 91-105 (2003). (Pubitemid 37088581)
66. Gregerson, D. S., Heuss, N. D., Lew, K. L., McPherson, S. W. & Ferrington, D. A. Interaction of retinal pigmented epithelial cells and CD4 T cells leads to T-cell anergy. Invest. Ophthalmol. Vis. Sci. 48, 4654-4663 (2007). (Pubitemid 351260983)
67. Prendergast, R. A. et al. T cell traffic and the inflammatory response in experimental autoimmune uveoretinitis. Invest. Ophthalmol. Vis. Sci. 39, 754-762 (1998). (Pubitemid 28207470)
68. Sugita, S. & Streilein, J. W. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 198, 161-171 (2003). (Pubitemid 36870196)
69. Sugita, S., Ng, T. F., Schwartzkopff, J. & Streilein, J. W. CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express their own B7-2 to achieve global suppression of T cell activation. J. Immunol. 172, 4184-4194 (2004). (Pubitemid 38375231)
70. Yoshida, M., Kezuka, T. & Streilein, J. W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 2. Generation of TGF-β-producing regulatory T cells. Invest. Ophthalmol. Vis. Sci. 41, 3862-3870 (2000).
71. Sugita, S. et al. B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest. Ophthalmol. Vis. Sci. 47, 5376-5384 (2006). (Pubitemid 46723788)
72. Yoshida, M., Takeuchi, M. & Streilein, J. W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 1. Inhibition of T-cell activation in vitro by direct cell-to-cell contact. Invest. Ophthalmol. Vis. Sci. 41, 811-821 (2000). (Pubitemid 30158893)
73. Taylor, A. W., Alard, P., Yee, D. G. & Streilein, J. W. Aqueous humor induces transforming growth factor-β (TGF-β)-producing regulatory T-cells. Curr. Eye Res. 16, 900-908 (1997). (Pubitemid 27410073)
74. Taylor, A. W., Yee, D. G. & Streilein, J. W. Suppression of nitric oxide generated by inflammatory macrophages by calcitonin gene-related peptide in aqueous humor. Invest. Ophthalmol. Vis. Sci. 39, 1372-1378 (1998). (Pubitemid 28307362)
75. Taylor, A. W., Streilein, J. W. & Cousins, S. W. Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J. Immunol. 153, 1080-1086 (1994). (Pubitemid 24228499)
76. D'Orazio, T. J., DeMarco, B. M., Mayhew, E. S. & Niederkorn, J. Y. Effect of aqueous humor on apoptosis of inflammatory cell types. Invest. Ophthalmol. Vis. Sci. 40, 1418-1426 (1999). (Pubitemid 29252332)
77. Zhou, R., Horai, R., Mattapallil, M. J. & Caspi, R. R. A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid. J. Immunol. 187, 4170-4177 (2011).
78. Mo, J. S. & Streilein, J. W. Immune privilege persists in eyes with extreme inflammation induced by intravitreal LPS. Eur. J. Immunol. 31, 3806-3815 (2001). (Pubitemid 34030995)
79. Ohta, K., Wiggert, B., Yamagami, S., Taylor, A. W. & Streilein, J. W. Analysis of immunomodulatory activities of aqueous humor from eyes of mice with experimental autoimmune uveitis. J. Immunol. 164, 1185-1192 (2000). (Pubitemid 30067228)
80. Ohta, K., Yamagami, S., Taylor, A. W. & Streilein, J. W. IL-6 antagonizes TGF-β and abolishes immune privilege in eyes with endotoxin-induced uveitis. Invest. Ophthalmol. Vis. Sci. 41, 2591-2599 (2000). (Pubitemid 30624387)
81. Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nature Rev. Immunol. 13, 23-33 (2013).
82. Moffett, A. & Loke, C. Immunology of placentation in eutherian mammals. Nature Rev. Immunol. 6, 584-594 (2006). (Pubitemid 44134091)
83. Kovats, S. et al. A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220-223 (1990). (Pubitemid 120031455)
84. Rouas-Freiss, N., Goncalves, R. M., Menier, C., Dausset, J. & Carosella, E. D. Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc. Natl Acad. Sci. USA 94, 11520-11525 (1997). (Pubitemid 27451031)
85. Fournel, S. et al. Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J. Immunol. 164, 6100-6104 (2000). (Pubitemid 30408785)
86. Carosella, E. D., Moreau, P., Aractingi, S. & Rouas-Freiss, N. HLA-G: a shield against inflammatory aggression. Trends Immunol. 22, 553-555 (2001). (Pubitemid 33016401)
87. Ristich, V., Liang, S., Zhang, W., Wu, J. & Horuzsko, A. Tolerization of dendritic cells by HLA-G. Eur. J. Immunol. 35, 1133-1142 (2005). (Pubitemid 40542220)
88. Chang, C. C. et al. Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nature Immunol. 3, 237-243 (2002). (Pubitemid 34218114)
89. Sacks, G. P., Clover, L. M., Bainbridge, D. R., Redman, C. W. & Sargent, I. L. Flow cytometric measurement of intracellular Th1 and Th2 cytokine production by human villous and extravillous cytotrophoblast. Placenta 22, 550-559 (2001). (Pubitemid 32700839)
90. Liu, F. et al. Placental trophoblasts shifted Th1/Th2 balance toward Th2 and inhibited Th17 immunity at fetomaternal interface. APMIS 119, 597-604 (2011).
91. Schumacher, A. et al. Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J. Immunol. 182, 5488-5497 (2009).
92. Siiteri, P. K. & Stites, D. P. Immunologic and endocrine interrelationships in pregnancy. Biol. Reprod. 26, 1-14 (1982). (Pubitemid 12130605)
93. Piccinni, M. P. et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J. Immunol. 155, 128-133 (1995).
94. Zorzi, W. et al. Demonstration of the expression of CD95 ligand transcript and protein in human placenta. Placenta 19, 269-277 (1998). (Pubitemid 28224795)
95. Jerzak, M. & Bischof, P. Apoptosis in the first trimester human placenta: the role in maintaining immune privilege at the maternal-foetal interface and in the trophoblast remodelling. Eur. J. Obstet. Gynecol. Reprod. Biol. 100, 138-142 (2002). (Pubitemid 34028130)
96. Hsi, B. L., Hunt, J. S. & Atkinson, J. P. Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells. J. Reprod. Immunol. 19, 209-223 (1991).
97. Petroff, M. G. et al. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol. Reprod. 68, 1496-1504 (2003). (Pubitemid 36519751)
98. Suzuki, K. & Tomasi, T. B. Jr. Mechanism of immune suppression by murine neonatal fluids. J. Immunol. 125, 1806-1810 (1980). (Pubitemid 10018601)
99. Wilbanks, G. A. & Streilein, J. W. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-β. Eur. J. Immunol. 22, 1031-1036 (1992).
100. Shohat, B. & Faktor, J. M. Immunosuppressive activity of human amniotic fluid of normal and abnormal pregnancies. Int. J. Fertil. 33, 273-277 (1988).
101. Murgita, R. A. & Tomasi, T. B. Jr. Suppression of the immune response by α-fetoprotein on the primary and secondary antibody response. J. Exp. Med. 141, 269-286 (1975).
102. Pressman, E. K. et al. Inflammatory cytokines and antioxidants in midtrimester amniotic fluid: correlation with pregnancy outcome. Am J. Obstet Gynecol. 204, 155.e1-155.e7 (2011).
103. Mital, P., Hinton, B. T. & Dufour, J. M. The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol. Reprod. 84, 851-858 (2011).
104. Fijak, M. & Meinhardt, A. The testis in immune privilege. Immunol. Rev. 213, 66-81 (2006). (Pubitemid 44401494)
105. Mital, P., Kaur, G. & Dufour, J. M. Immunoprotective sertoli cells: making allogeneic and xenogeneic transplantation feasible. Reproduction 139, 495-504 (2010).
106. Suarez-Pinzon, W. et al. Testicular sertoli cells protect islet β-cells from autoimmune destruction in NOD mice by a transforming growth factor-β1-dependent mechanism. Diabetes 49, 1810-1818 (2000).
107. Sipione, S. et al. Identification of a novel human granzyme B inhibitor secreted by cultured sertoli cells. J. Immunol. 177, 5051-5058 (2006). (Pubitemid 44527575)
108. Liva, S. M. & Voskuhl, R. R. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J. Immunol. 167, 2060-2067 (2001). (Pubitemid 32747513)
109. Skinner, M. K. & Moses, H. L. Transforming growth factor β gene expression and action in the seminiferous tubule: peritubular cell-Sertoli cell interactions. Mol. Endocrinol. 3, 625-634 (1989). (Pubitemid 19108940)
110. Gerdprasert, O. et al. Expression of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor in normal and inflamed rat testis. Mol. Hum. Reprod. 8, 518-524 (2002). (Pubitemid 34746284)
111. Piquet-Pellorce, C., Dorval-Coiffec, I., Pham, M. D. & Jegou, B. Leukemia inhibitory factor expression and regulation within the testis. Endocrinology 141, 1136-1141 (2000). (Pubitemid 32260456)
112. Breucker, H. Macrophages, a normal component in seasonally involuting testes of the swan, Cygnus olor. Cell Tissue Res. 193, 463-471 (1978). (Pubitemid 9049256)
113. Naito, M. & Itoh, M. Patterns of infiltration of lymphocytes into the testis under normal and pathological conditions in mice. Am. J. Reprod. Immunol. 59, 55-61 (2008). (Pubitemid 350285583)
114. Naito, M. et al. Histopathology of the tubuli recti at the start of experimental autoimmune orchitis in mice. Med. Mol. Morphol. 42, 230-235 (2009).
115. Schmorl, C. in Pathologisch-anatomische Untersuchungen uber Puerperal-Eklampsie Verlag von F.C.W. Vogel (1893).
116. Reynolds, A. G. Placental metastasis from malignant melanoma; report of a case. Obstet. Gynecol. 6, 205-209 (1955).
117. Schroder, J. & De la Chapelle, A. Fetal lymphocytes in the maternal blood. Blood 39, 153-162 (1972).
118. Loubiere, L. S. et al. Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Lab Invest. 86, 1185-1192 (2006). (Pubitemid 44624154)
119. Khosrotehrani, K., Johnson, K. L., Cha, D. H., Salomon, R. N. & Bianchi, D. W. Transfer of fetal cells with multilineage potential to maternal tissue. JAMA 292, 75-80 (2004). (Pubitemid 38923796)
120. Srivatsa, B. Srivatsa, S., Johnson, K. L. & Bianchi, D. W. Maternal cell microchimerism in newborn tissues. J. Pediatr. 142, 31-35 (2003). (Pubitemid 36106384)
121. O'Donoghue, K. et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 364, 179-182 (2004). (Pubitemid 38891690)
122. Evans, P. C. et al. Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 93, 2033-2037 (1999). (Pubitemid 29128506)
123. Nelson, J. L. et al. Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism. Proc. Natl Acad. Sci. USA 104, 1637-1642 (2007). (Pubitemid 46214643)
124. Maloney, S. et al. Microchimerism of maternal origin persists into adult life. J. Clin. Invest. 104, 41-47 (1999). (Pubitemid 29534343)
125. Isoda, T. et al. Immunologically silent cancer clone transmission from mother to offspring. Proc. Natl Acad. Sci. USA 106, 17882-17885 (2009).
126. Stevens, A. M., Hermes, H. M., Rutledge, J. C., Buyon, J. P. & Nelson, J. L. Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 362, 1617-1623 (2003). (Pubitemid 37443529)
127. Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562-1565 (2008).
128. Nijagal, A. et al. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J. Clin. Invest. 121, 582-592 (2011).
129. Burlingham, W. J. A lesson in tolerance-maternal instruction to fetal cells. N. Engl. J. Med. 360, 1355-1357 (2009).
130. Chen, C. P. et al. Trafficking of multipotent mesenchymal stromal cells from maternal circulation through the placenta involves vascular endothelial growth factor receptor-1 and integrins. Stem Cells 26, 550-561 (2008).
131. Chadwick, V. S. et al. Production of peptides inducing chemotaxis and lysosomal enzyme release in human neutrophils by intestinal bacteria in vitro and in vivo. Scand. J. Gastroenterol. 23, 121-128 (1988). (Pubitemid 18067041)
132. Arques, J. L. et al. Salmonella induces flagellin-and MyD88-dependent migration of bacteria-capturing dendritic cells into the gut lumen. Gastroenterology 137, 579-587.e2 (2009).
133. Rescigno, M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol. 32, 256-264 (2011).
134. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunol. 6, 507-514 (2005). (Pubitemid 41716764)
135. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812-826 (2007). (Pubitemid 46915505)
136. Xu, W. et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 8, 294-303 (2007). (Pubitemid 46745379)
137. Iliev, I. D. et al. Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 58, 1481-1489 (2009).
138. Ramakrishnan, L. Revisiting the role of the granuloma in tuberculosis. Nature Rev. Immunol. 12, 352-366 (2012).
139. Mustafa, T., Mogga, S. J., Mfinanga, S. G., Morkve, O. & Sviland, L. Immunohistochemical analysis of cytokines and apoptosis in tuberculous lymphadenitis. Immunology 117, 454-462 (2006).
140. Popov, A. et al. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J. Clin. Invest. 116, 3160-3170 (2006). (Pubitemid 44878630)
141. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749-752 (2010).