Chapter 14 : Toll-Like Receptors and Control of Adaptive Immunity

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Toll-Like Receptors and Control of Adaptive Immunity, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap14-1.gif /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap14-2.gif


This chapter focuses on how pattern recognition is used by the innate immune system to distinguish self from nonself and how this discrimination is translated into induction of adaptive immunity. The past few years have seen significant advances in our understanding of how adaptive immune responses are controlled by the initial innate recognition of microbial infection. In particular, the identification of the Toll-like receptor (TLR) family as the critical receptor family involved in the recognition of infectious nonself has enabled researchers to examine the mechanisms by which adaptive responses are controlled by the innate immune system. Before discussing the specific mechanisms by which TLRs control adaptive immunity, the chapter talks about the general mechanisms by which self/nonself discrimination is regulated within the adaptive immune system. The second half of the chapter focuses on how TLRs control some of these mechanisms and link microbial recognition to self and nonself discrimination by the adaptive immune system. Upon activation, lymphocytes undergo a period of rapid proliferation. The innate immune system keeps the infection in check long enough for lymphocytes to expand and eventually eliminate the microbial challenge. Immature B cells that have receptors capable of recognizing membrane-bound selfantigens receive signals leading to apoptosis of the self-reactive B lymphocyte. IgG2 antibodies are effective at eliminating a variety of intracellular and extracellular pathogens because they can fix complement and direct the lysis of infected cells in a process called antibody-dependent cellular cytotoxicity.

Citation: Barton G, Pasare C, Medzhitov R. 2004. Toll-Like Receptors and Control of Adaptive Immunity, p 271-285. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch14

Key Concept Ranking

Innate Immune System
Adaptive Immune System
Immune Systems
Major Histocompatibility Complex
Immune Receptors
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Control of DC maturation by TLRs. Microbial infection is recognized by immature DCs in the tissues when TLRs are activated. Signals initiated by TLRs lead to DC maturation, which includes migration to secondary lymphoid organs, upregulation of MHC and costimulatory molecules, and production of cytokines.

Citation: Barton G, Pasare C, Medzhitov R. 2004. Toll-Like Receptors and Control of Adaptive Immunity, p 271-285. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch14
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Control of T regulatory cell function by TLRs. Treg cells suppress activation of naive T cells and prevent responses to self-antigens. During an infection, TLR ligation on DCs leads to upregulation of MHC and costimulatory molecules as well as production of cytokines such as IL-6. IL-6 provides signals to effector T cells (Te) that render them resistant to the effects of Treg cells, allowing T-cell activation to proceed.

Citation: Barton G, Pasare C, Medzhitov R. 2004. Toll-Like Receptors and Control of Adaptive Immunity, p 271-285. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch14
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Innate immune recognition controls induction of differential immune responses. Microbes that engage TLRs induce a characteristic adaptive immune response leading to Th1 T-cell differentiation and the production of IgG2 antibodies. Large multicellular pathogens, such as worms, induce Th2 T-cell differentiation and the production of IgE antibodies. How innate recognition of worms is achieved and how this recognition leads to induction of Th2 differentiation remain unclear.

Citation: Barton G, Pasare C, Medzhitov R. 2004. Toll-Like Receptors and Control of Adaptive Immunity, p 271-285. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch14
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Alonzi, T.,, E. Fattori,, D. Lazzaro,, P. Costa,, L. Probert,, G. Kollias,, F. De Benedetti,, V. Poli,, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461468.
2. Anderson, M. S.,, E. S. Venanzi,, L. Klein,, Z. Chen,, S. P. Berzins,, S. J. Turley,, H. von Boehmer,, R. Bronson,, A. Dierich,, C. Benoist,, and D. Mathis. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:13951401.
3. Asano, M.,, M. Toda,, N. Sakaguchi,, and S. Sakaguchi. 1996. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184:387396.
4. Asselin-Paturel, C.,, A. Boonstra,, M. Dalod,, I. Durand,, N. Yessaad,, C. Dezutter-Dambuyant,, A. Vicari,, A. O'Garra,, C. Biron,, F. Briere,, and G. Trinchieri. 2001. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2:11441150.
5. Banchereau, J.,, and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245252.
6. Borriello, F.,, M. P. Sethna,, S. D. Boyd,, A. N. Schweitzer,, E. A. Tivol,, D. Jacoby,, T. B. Strom,, E. M. Simpson,, G. J. Freeman,, and A. H. Sharpe. 1997. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6:303313.
7. Brunner, T.,, R. J. Mogil,, D. LaFace,, N. J. Yoo,, A. Mahboubi,, F. Echeverri,, S. J. Martin,, W. R. Force,, D. H. Lynch,, C. F. Ware,, and D. R. Green. 1995. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:441444.
8. Chen, Y.,, V. K. Kuchroo,, J. Inobe,, D. A. Hafler,, and H. L. Weiner. 1994. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:12371240.
9. Cresswell, P.,, N. Bangia,, T. Dick,, and G. Diedrich. 1999.The nature of the MHC class I peptide loading complex. Immunol. Rev. 172:2128.
10. Cyster, J. G.,, S. B. Hartley,, and C. C. Goodnow. 1994. Competition for follicular niches excludes selfreactive cells from the recirculating B-cell repertoire. Nature 371:389395.
11. Dalod, M.,, T. P. Salazar-Mather,, L. Malmgaard,, C. Lewis,, C. Asselin-Paturel,, F. Briere,, G. Trinchieri,, and C. A. Biron. 2002. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195:517528.
12. Dhein, J.,, H. Walczak,, C. Baumler,, K. M. Debatin,, and P. H. Krammer. 1995. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:438441.
13. Diefenbach, A.,, and D. H. Raulet. 2001. Strategies for target cell recognition by natural killer cells. Immunol. Rev. 181:170184.
14. Drakesmith, H.,, B. Chain,, and P. Beverley. 2000. How can dendritic cells cause autoimmune disease? Immunol.Today 21:214217.
15. Fontenot, J.D.,, M.A. Gavin,, and A.Y. Rudensky. 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4:330336.
16. Goodnow, C. C.,, J. Crosbie,, S. Adelstein,, T. B. Lavoie,, S. J. Smith-Gill,, D. Y. Mason,, H. Jorgensen,, R.A. Brink,, H. Pritchard-Briscoe,, M. Loughnan,, and R. H. Loblay,, R. J. Trent,, and A. Basten. 1989. Clonal silencing of self-reactive B lymphocytes in a transgenic mouse model. Cold Spring Harbor Symp. Quant. Biol. 54(Pt. 2):907920.
17. Gorelik, L.,, and R. A. Flavell. 2002.Transforming growth factor-beta in T-cell biology. Nat. Rev. Immunol. 2:4653.
18. Groux, H.,, A. O'Garra,, M. Bigler,, M. Rouleau,, S. Antonenko,, J. E. de Vries,, and M. G. Roncarolo. 1997. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737742.
19. Hartley, S. B.,, J. Crosbie,, R. Brink,, A. B. Kantor,, A. Basten,, and C. C. Goodnow. 1991. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353:765769.
20. Hori, S.,, T. Nomura,, and S. Sakaguchi. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:10571061.
21. Huang, Q.,, D. Liu,, P. Majewski,, L. C. Schulte,, J. M. Korn,, R. A. Young,, E. S. Lander,, and N. Hacohen. 2001. The plasticity of dendritic cell responses to pathogens and their components. Science 294:870875.
22. Janeway, C.A., Jr. 1989.Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54(Pt 1):113.
23. Janeway, C. A., Jr.,, P. Travers,, M. Walport,, and M. Schlomchik. 2001. Immunobiology: the Immune System in Health and Disease, 5th ed. Garland Publishing, New York, N.Y.
24. Jenkins, M. K.,, and R. H. Schwartz. 1987.Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165:302319.
25. Ju, S. T.,, D. J. Panka,, H. Cui,, R. Ettinger,, M. el-Khatib,, D. H. Sherr,, B. Z. Stanger,, and A. Marshak-Rothstein. 1995. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373:444448.
26. Kadowaki, N.,, S. Ho,, S. Antonenko,, R. W. Malefyt,, R. A. Kastelein,, F. Bazan,, and Y. J. Liu. 2001. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194:863869.
27. Kawabe, T.,, T. Naka,, K. Yoshida,, T. Tanaka,, H. Fujiwara,, S. Suematsu,, N. Yoshida,, T. Kishimoto,, and H. Kikutani. 1994. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1:167178.
28. Khattri, R.,, T. Cox,, S. A. Yasayko,, and F. Ramsdell. 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4:337342.
29. Kuhn, R.,, J. Lohler,, D. Rennick,, K. Rajewsky,, and W. Muller. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263274.
30. Lantz, O.,, I. Grandjean,, P. Matzinger,, and J. P. Di Santo. 2000. Gamma chain required for naive CD4+ T cell survival but not for antigen proliferation. Nat. Immunol. 1:5458.
31. Liston, A.,, S. Lesage,, J. Wilson,, L. Peltonen,, and C. C. Goodnow. 2003. Aire regulates negative selec- tion of organ-specific T cells. Nat. Immunol. 4:350354.
32. Liu, Y.,, and C. A. Janeway, Jr. 1992. Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc. Natl. Acad. Sci. USA 89:38453849.
33. Maizels, R. M.,, and M. Yazdanbakhsh. 2003. Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat. Rev. Immunol. 3:733744.
34. Medzhitov, R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1:135145.
35. Medzhitov, R.,, and C. A. Janeway, Jr. 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295298.
36. Mellman, I.,, S. J. Turley,, and R. M. Steinman. 1998.Antigen processing for amateurs and professionals. Trends Cell. Biol. 8:231237.
37. Murphy, K. M.,, W. Ouyang,, J. D. Farrar,, J. Yang,, S. Ranganath,, H. Asnagli,, M. Afkarian,, and T. L. Murphy. 2000. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18:451494.
38. Nakagawa, T.Y.,, and A.Y. Rudensky. 1999. The role of lysosomal proteinases in MHC class II-mediated antigen processing and presentation. Immunol. Rev. 172:121129.
39. Ohshima, S.,, Y. Saeki,, T. Mima,, M. Sasai,, K. Nishioka,, S. Nomura,, M. Kopf,, Y. Katada,, T. Tanaka,, M. Suemura,, and T. Kishimoto. 1998. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl. Acad. Sci. USA 95:82228226.
40. Pasare, C.,, and R. Medzhitov. 2003.Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:10331036.
41. Raulet, D. H.,, R. E. Vance,, and C.W. McMahon. 2001. Regulation of the natural killer cell receptor repertoire. Annu. Rev. Immunol. 19:291330.
42. Ravetch, J. V.,, and L. L. Lanier. 2000. Immune inhibitory receptors. Science 290:8489.
43. Richards, H. B.,, M. Satoh,, M. Shaw,, C. Libert,, V. Poli,, and W. H. Reeves. 1998. Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristine-induced lupus. J. Exp. Med. 188:985990.
44. Rose, N. R. 1998.The role of infection in the pathogenesis of autoimmune disease. Semin.Immunol. 10:513.
45. Sadlack, B.,, H. Merz,, H. Schorle,, A. Schimpl,, A. C. Feller,, and I. Horak. 1993. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:253261.
46. Sadlack, B.,, J. Lohler,, H. Schorle,, G. Klebb,, H. Haber,, E. Sickel,, R. J. Noelle,, and I. Horak. 1995. Generalized autoimmune disease in interleukin-2- deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25:30533059.
47. Sakaguchi, S.,, N. Sakaguchi,, M. Asano,, M. Itoh,, and M. Toda. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:11511164.
48. Samoilova, E. B.,, J. L. Horton,, B. Hilliard,, T. S. Liu,, and Y. Chen. 1998. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161:64806486.
49. Sasai, M.,, Y. Saeki,, S. Ohshima,, K. Nishioka,, T. Mima,, T. Tanaka,, Y. Katada,, K. Yoshizaki,, M. Suemura,, and T. Kishimoto. 1999. Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum. 42: 16351643.
50. Schwartz, R. H. 2003. T cell anergy. Annu. Rev. Immunol. 21:305334.
51. Seder, R. A.,, and R. Ahmed. 2003. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat. Immunol. 4:835842.
52. Shahinian, A.,, K. Pfeffer,, K. P. Lee,, T.M. Kundig,, K. Kishihara,, A. Wakeham,, K. Kawai,, P. S. Ohashi,, C. B. Thompson,, and T.W. Mak. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261:609612.
53. Shull, M. M.,, I. Ormsby,, A. B. Kier,, S. Pawlowski,, R. J. Diebold,, M. Yin,, R. Allen,, C. Sidman,, G. Proetzel,, D. Calvin,, N. Annunziata,, and T. Doetschman. 1992.Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693699.
54. Starr, T. K.,, S. C. Jameson,, and K. A. Hogquist. 2003. Positive and negative selection of T cells. Annu. Rev. Immunol. 21:139176.
55. Steinman, R. M.,, D. Hawiger,, and M. C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21:685711.
56. Takeda, K.,, T. Kaisho,, and S. Akira. 2003.Toll-like receptors. Annu. Rev. Immunol. 21:335376.
57. Teague, T. K.,, P. Marrack,, J. W. Kappler,, and A. T. Vella. 1997. IL-6 rescues resting mouse T cells from apoptosis. J. Immunol. 158:57915796.
58. Thornton, A. M.,, and E. M. Shevach. 1998. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188:287296.
59. Tonegawa, S. 1983. Somatic generation of antibody diversity. Nature 302:575581.
60. Tough, D. F.,, P. Borrow,, and J. Sprent. 1996. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272:19471950.
61. Zheng, L.,, G. Fisher,, R. E. Miller,, J. Peschon,, D. H. Lynch,, and M. J. Lenardo. 1995. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377:348351.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error