CO-INHIBITORY MOLECULES IN NORMAL AND PATHOLOGICAL CONDITIONS. IMMONOLOGICAL CHECKPOINTS Part 1. Role of co-inhibitory molecules in normal immune response and in allergy and autoimmune diseases

Cover Page

Cite item

Full Text

Abstract

The differentiation and protective capacity of antigen-specific T-cells are regulated by both positive and negative signals. Molecules of the B 7/CD 28 family are very important for regulating T-cell activation and peripheral tolerance. In particular, PD-1, CTLA-4 and other co-inhibitory molecules play an active role in dampening of excessive immune activation which is critical for successful clearance of a pathogen without harm to the host. These co-inhibitory molecules (immunological checkpoints) are essential for inducible Treg differentiation and function. On the other hand, overexpression of co-inhibitory molecules can lead to T-cell exhaustion, an adaptive property that occurs in T-cells due to persistent systemic antigen exposure. Exhausted T-cells are described as effector T-cells with decreased cytokine expression and effector function. Here, we review a critical role of co-inhibitory molecules which they play in immunopathogenesis of four immunological syndromes: allergy, autoimmune diseases, chronic infection, and cancer. Reversal of exhausted T-cells by blocking co-inhibitory pathways has become an important area due to its therapeutic applications in oncology and chronic viral infections.

About the authors

A. P. Toptygina

G.N.Gabrichevsky Research Institute for Epidemiology and Microbiology; Lomonosov Moscow State University

Author for correspondence.
Email: toptyginaanna@rambler.ru

PhD, MD (Medicine), Leading Research Associate, Laboratory of Cytokines; Professor Chair of Immunology, Faculty of Biology

125212 Moscow, Admirala Makarova ul., 10

Russian Federation

References

  1. Ярилин А. А. Иммунология. М.: ГЭОТАР-Медия, 2010. – 752.
  2. Kenneth P., Murphy P. T., Walport M., Janeway C. Immunobiology. New York, NY: Garland Science, Taylor and Francis Group, LLC, 2008.
  3. Jenkins M. K. The ups and downs of T cell costimulation. Immunity. 1994, 1, 443-446.
  4. Yamane H., W. E. Paul Cytokines of the [gamma] c family control CD4 + T cell differentiation and function. Nat. Immunol. 2012, 13, 1037-1044.
  5. Green J. M., Noel P. J., Sperling A. I., Walunas T. L., Lenschow D. J., Stack R., Gray G. S., Bluestone J. A., Thompson C. B. T cell costimulation through the CD28 receptor. Proceedings of the Association of American Physicians. 1995,107,41-46.
  6. Greenfield E. A., Nguyen K. A., Kuchroo V. K. CD28/B7 costimulation: a review. Critical reviews in immunology. 1998, 18, 389-418.
  7. Boise L. H., Minn A. J., Noel P. J., June C. H., Accavitti M. A., Lindsten T., Thompson C. B. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity. 1995, 3, 87-98.
  8. Choi YS, Kageyama R., Eto D., Escobar T. C., Johnston R. J., Monticelli L., Lao C., Crotty S. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 2011, 34, 932-946.
  9. Leibson P. J. The regulation of lymphocyte activation by inhibitory receptors. Current Opinion in Immunology. 2004, 16(3), 328-336.
  10. Chen L. Co-inhibitory molecules of the B 7-CD28 family in the control of T-cell immunity. Nature Reviews Immunology. 2004, 4(5), 336-347.
  11. Zhu C., Anderson A. C., Kuchroo V. K. TIM-3 and its regulatory role in immune responses. Current topics in microbiology and immunology. 2011, 350, 1-15.
  12. Huard B., Gaulard P., Faure F., Hercend T., Triebel F. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics. 1994, 39(3), 213-217.
  13. Cai G., Freeman G. J. The CD160, BTLA, LIGHT/ HVEM pathway: a bidirectional switch regulating T-cell activation. Immunological Reviews. 2009, 229(1), 244-258.
  14. Rudd C. E., Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol. 2003, 3, 544-556.
  15. Walunas T. L., Lenschow D. J., Bakker C. Y., Linsley P. S., Freeman G. J., Green J. M., Thompson C. B., Bluestone J. A. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994, 1, 405-413.
  16. Doty R. T., Clark E. A. Two regions in the CD80 cytoplasmic tail regulate CD80 redistribution and T cell costimulation. J Immunol. 1998, 161, 2700-2707.
  17. Yokosuka T., Kobayashi W., Takamatsu M., Sakata-Sogawa K., Zeng H., Hashimoto-Tane A., Yagita H., Tokunaga M., Saito T. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 2010, 33, 326-39.
  18. Qureshi O. S., Zheng Y., Nakamura K., Attridge K., Manzotti C., Schmidt E. M., Baker J., Jeffery L. E., Kaur S., Briggs Z., Hou T. Z., Futter C. E., Anderson G., Walker L. S., Sansom D. M. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011, 332, 600-603.
  19. Mackay C. R., Marston W. L., Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. Journal of Experimental Medicine. 1990, 171(3), 801-817.
  20. Badovinac V. P., Harty J. T. Programming, demarcating, and manipulating CD8 + T-cell memory. Immunological Reviews. 2006, 211, 67-80.
  21. Chambers C. A., Kuhns M. S., Egen J. G., Allison J. P. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annual Review of Immunology. 2001, 19, 565-594.
  22. Hildeman D. A., Zhu Y., Mitchell T. C., Kappler J., Marrack P. Molecular mechanisms of activated T cell death in vivo. Current Opinion in Immunology. 2002, 14(3), 354-359.
  23. Iezzi G., Karjalainen K., Lanzavecchia A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity. 1998, 8(1), 89-95.
  24. Salomon B., Bluestone J. A. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annual Review of Immunology. 2001, 19, 225-252.
  25. Kong K. F., Fu G., Zhang Y., Yokosuka T., Casas J., Canonigo-Balancio A.J., Becart S., Kim G., Yates 3rd J.R., Kronenberg M., Saito T., Gascoigne N. R., Altman A. Protein kinase C-theta controls CTLA-4-mediated regulatory T cell function. Nat Immunol. 2014, 15, 465-472.
  26. Miska J., Abdulreda M. H., Devarajan P., Lui J. B., Suzuki J., Pileggi A., Berggren P. O., Chen Z. Realtime immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance. J Exp Med. 2014, 211, 441-456.
  27. Onishi Y., Fehervari Z., Yamaguchi T., Sakaguchi S. Foxp3 + natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A. 2008, 105, 10113-10118.
  28. Oderup C., Cederbom L., Makowska A., Cilio C. M., Ivars F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4 + CD25 + regulatory T-cellmediated suppression. Immunology. 2006, 118, 240-249.
  29. Greenwald R. J., Freeman G. J., Sharpe A. H. The B 7 family revisited. Annual Review of Immunology. 2005, 23, 515-548.
  30. Nakae S., Suto H., Iikura M., Kakurai M., Sedgwick J. D., Tsai M., Galli S. J. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. Journal of Immunology. 2006, 176(4), 2238-2248.
  31. Keir M. E., Butte M. J., Freeman G. J., Sharpe A. H. PD-1 and its ligands in tolerance and immunity Annual review of immunology. 2008, 26, 677-704.
  32. Ishida M., Iwai Y., Tanaka Y., Okazaki T., Freeman G. J., Minato N., Honjo T. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunology Letters. 2002, 84(1), 57-62.
  33. Butte M. J., Keir M. E., Phamduy T. B., Sharpe A. H., Freeman G. J. Programmed death-1 ligand 1 interacts specifically with the B 7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007, 27, 111-122.
  34. Kinter A. L., Godbout E. J., McNally J.P., Sereti I., Roby G. A., O’Shea M.A., Fauci A. S. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008, 181, 6738-6746.
  35. Yusuf I., Kageyama R., Monticelli L., Johnston R. J., Ditoro D., Hansen K., Barnett B., Crotty S. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150) J Immunol. 2010, 185, 190-202.
  36. Good-Jacobson K.L., Szumilas C. G., Chen L., Sharpe A. H., Tomayko M. M., Shlomchik M. J. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells Nat Immunol. – 2010, 11, 535-542.
  37. Parry R. V., Chemnitz J. M., Frauwirth K. A., Lanfranco A. R., Braunstein I., Kobayashi S. V., Linsley P. S., Thompson C. B., Riley J. L. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Molecular and cellular biology. 2005, 25, 9543-9553.
  38. Wang L., Pino-Lagos K., de Vries V. C., Guleria I., Sayegh M. H., Noelle R. J. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3 + CD4 + regulatory T cells. Proc Natl Acad Sci USA. 2008, 105, 9331-9336.
  39. Guleria I., Khosroshahi A., Ansari M. J., Habicht A., Azuma M., Yagita H., Noelle R. J., Coyle A., Mellor A. L., Khoury S. J., Sayegh M. H. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med. – 2005, 202, 231-237.
  40. Watanabe N., Gavrieli M., Sedy J. R., Yang J., Fallarino F., Loftin S. K., Hurchla M. A., Zimmerman N., Sim J., Zang X., Murphy T. L., Russell J. H., Allison J. P., Murphy K. M. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature immunology. 2003, 4, 670-679.
  41. Steinberg M. W., Cheung T. C., Ware C. F. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunological reviews. 2011, 244, 169-187.
  42. Cheung T. C., Oborne L. M., Steinberg M. W., Macauley M. G., Fukuyama S., Sanjo H., D’Souza C., Norris P. S., Pfeffer K., Murphy K. M., Kronenberg M., Spear P. G., Ware C. F. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. J Immunol. 2009, 183, 7286-7296.
  43. Zhu C., Anderson A. C., Schubart A., Xiong H., Imitola J., Khoury S. J., Zheng X. X., Strom T. B., Kuchroo V. K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005, 6, 1245-1252.
  44. Wada J., Ota K., Kumar A., Wallner E. I., Kanwar Y. S. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997, 99, 2452-2461.
  45. Wang F., Wan L., Zhang C., Zheng X., Li J., Chen Z. K. Tim-3-Galectin-9 pathway involves the suppression induced by CD4 + CD25 + regulatory T cells. Immunobiology. 2009, 214, 342-349.
  46. Wang F., He W., Zhou H., Yuan J., Wu K., Xu L., Chen Z. K. The Tim-3 ligand galectin-9 negatively regulates CD8 + alloreactive T cell and prolongs survival of skin graft. Cell Immunol. 2007, 250, 68-74.
  47. Baixeras E., Huard B., Miossec C., Jitsukawa S., Martin M., Hercend T., Auffray C., Triebel F., Piatier-Tonneau D. Characterization of the lymphocyte activation gene 3–encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 1992, 176, 327-337.
  48. Workman C. J., Vignali D. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 2005, 174, 688-695.
  49. Workman C. J., Wang Y., El Kasmi K. C., Pardoll D. M., Murray P. J., Drake C. G., Vignali D. A. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J. Immunol. 2009, 182, 1885-1891.
  50. Workman C. J., Dugger K. J., Vignali D. A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 2002, 169, 5392-5395.
  51. Wang L., Rubinstein R., Lines J. L., Wasiuk A., Ahonen C., Guo Y., Lu L. F., Gondek D., Wang Y., Fava R. A., Fiser A., Almo S., Noelle R. J. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 2011, 208, 577-592.
  52. van Noort J. M., van Sechel A., Boon J., Boersma W. J., Polman C. H., Lucas C. J. Minor myelin proteins can be major targets for peripheral blood T cells from both multiple sclerosis patients and healthy subjects. J Neuroimmunol. 1993, 46, 67-72.
  53. Lohmann T., Leslie R. D., Londei M. T cell clones to epitopes of glutamic acid decarboxylase 65 raised from normal subjects and patients with insulin-dependent diabetes. J Autoimmun. 1996, 9, 385-389.
  54. Fontenot J. D., Rasmussen J. P., Williams L. M., Dooley J. L., Farr A. G., Rudensky A. Y. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005, 22, 329-341.
  55. Rubtsov Y. P., Rudensky A. Y. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 2007, 7, 443-453.
  56. Rubtsov Y. P., Rasmussen J. P., Chi E. Y., Fontenot J., Castelli L., Ye X., Treuting P., Siewe L., Roers A., Henderson Jr W. R., Muller W., Rudensky A. Y. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008, 28, 546-558.
  57. Collison L. W., Workman C. J., Kuo T. T., Boyd K., Wang Y., Vignali K. M., Cross R., Sehy D., Blumberg R. S., Vignali D. A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007, 450, 566-569.
  58. Gondek D. C., Lu L. F., Quezada S. A., Sakaguchi S., Noelle R. J. Cutting edge: contact-mediated suppression by CD4 + CD25 + regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol. 2005, 174, 1783-1786.
  59. Francisco L. M., Salinas V. H., Brown K. E., Vanguri V. K., Freeman G. J., Kuchroo V. K., Sharpe A. H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009, 206, 3015-3029.
  60. Yao S., Wang S., Zhu Y., Luo L., Zhu G., Flies S., Xu H., Ruff W., Broadwater M., Choi I. H., Tamada K., Chen L. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009, 113, 5811-5818.
  61. Vignali D. A., Collison L. W., Workman C. J. How regulatory T cells work. Nat Rev Immunol. 2008, 8, 523-532.
  62. Green E. A., Gorelik L., McGregor C.M., Tran E. H., Flavell R. A. CD4 + CD25 + T regulatory cells control anti-islet CD8 + T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA. 2003, 100, 10878-10883.
  63. Kukreja A., Cost G., Marker J., Zhang C., Sun Z., Lin-Su K., Ten S., Sanz M., Exley M., Wilson B., Porcelli S., Maclaren N. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002, 109, 131-140.
  64. McGeachy M.J., Stephens L. A., Anderton S. M. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4 + CD25 + regulatory cells within the central nervous system. J Immunol. 2005, 175, 3025-3032.
  65. Eastaff-Leung N., Mabarrack N., Barbour A., Cummins A., Barry S. Foxp3(+) Regulatory T Cells, Th17 Effector Cells, and Cytokine Environment in Inflammatory Bowel Disease. J Clin Immunol. 2010, 30, 80-89.
  66. Wright G. P., Notley C. A., Xue S. A., Bendle G. M., Holler A., Schumacher T. N., Ehrenstein M. R., Stauss H. J. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci USA. 2009, 106, 19078-19083.
  67. Ehrenstein M. R., Evans J. G., Singh A., Moore S., Warnes G., Isenberg D. A., Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004, 200, 277-285.
  68. Martin-Orozco N., Wang Y. H., Yagita H., Dong C. Cutting Edge: Programmed death (PD) ligand-1/ PD-1 interaction is required for CD8 + T cell tolerance to tissue antigensJ Immunol. 2006, 177, 8291-8295.
  69. Cheng X., Zhao Z., Ventura E., Gran B., Shindler K. S., Rostami A. The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma. J Neuroimmunol. 2007, 185, 75-86.
  70. Magnus T., Schreiner B., Korn T., Jack C., Guo H., Antel J., Ifergan I., Chen L., Bischof F., Bar-Or A., Wiendl H. Microglial expression of the B 7 family member B 7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS. J Neurosci. 2005, 25, 2537-2546.
  71. Kroner A., Mehling M., Hemmer B., Rieckmann P., Toyka K. V., Mäurer M., Wiendl H. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol. 2005, 58, 50-57.
  72. Wang C., Li Y., Proctor T. M., Vandenbark A. A., Offner H. Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis. J Neurosci Res. 2010, 88, 7-15.
  73. Nakazawa A., Dotan I., Brimnes J., Allez M., Shao L., Tsushima F., Azuma M., Mayer L. The expression and function of costimulatory molecules B 7H and B 7-H1 on colonic epithelial cells. Gastroenterology. 2004, 126, 1347-1357.
  74. Totsuka T., Kanai T., Makita S., Fujii R., Nemoto Y., Oshima S., Okamoto R., Koyanagi A., Akiba H., Okumura K., Yagita H., Watanabe M. Regulation of murine chronic colitis by CD4 + CD25 – programmed death-1+ T cells. Eur J Immunol. 2005, 35, 1773-1785.
  75. Totsuka T., Kanai T., Nemoto Y., Tomita T., Tsuchiya K., Sakamoto N., Okamoto R., Watanabe M. Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis. Eur J Immunol. 2008, 38, 1275-1286.
  76. Wan B., Nie H., Liu A., Feng G., He D., Xu R., Zhang Q., Dong C., Zhang J. Z. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006, 177, 8844-8850.
  77. Wang G., Hu P., Yang J., Shen G., Wu X. The effects of PDL-Ig on collagen-induced arthritis. Rheumatol Int. 2009, 177(12), 8844-8850.
  78. Roncarolo M. G., Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007, 7, 585-598.
  79. Galli S. J., Tsai M., Piliponsky A. M. The development of allergic inflammation. Nature. 2008, 454(7203), 445-454.
  80. Lewkowich I. P., Herman N. S., Schleifer K. W., Dance M. P., Chen B. L., Dienger K. M., Sproles A. A., Shah J. S., Kohl J., Belkaid Y., Wills-Karp M. CD4 + CD25 + T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med. 2005, 202, 1549-1561.
  81. Ling E. M., Smith T., Nguyen X. D., Pridgeon C., Dallman M., Arbery J., Carr V. A., Robinson D. S. Relation of CD4 + CD25 + regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004, 363, 608-615.
  82. Lajoie S., Lewkowich I. P., Suzuki Y., Clark J. R., Sproles A. A., Dienger K., Budelsky A. L., Wills-Karp M. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010, 11, 928-935.
  83. Kool M., van Nimwegen M., Willart M. A., Muskens F., Boon L., Smit J. J., Coyle A., Clausen B. E., Hoogsteden H. C., Lambrecht B. N., Hammad H. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol. 2009, 183, 1074-1082.
  84. McGee H.S., Yagita H., Shao Z., Agrawal D. K. PD-1 Antibody Blocks Therapeutic Effects of T-regulatory Cells in Cockroach Antigen-induced Allergic Asthma. Am J Respir Cell Mol Biol. 2009, 43(4), 432-442.
  85. Akbari O., Stock P., Singh A. K., Lombardi V., Lee W. L., Freeman G. J., Sharpe A. H., Umetsu D. T., Dekruyff R. H. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol. 2010, 3, 81-91.
  86. McAlees J. W., Lajoie S., Dienger K., Sproles A. A., Richgels P. K., Yang Y., Khodoun M., Azuma M., Yagita H., Fulkerson P. C., Wills-Karp M., Lewkowich I. P. Differential control of CD4 + T cell subsets by the PD-1/PD-L1 axis in allergic asthma. Eur J Immunol. 2015, 45(4), 1019-1029
  87. Matsumoto K., Fukuyama S., Eguchi-Tsuda M., Nakano T., Matsumoto T., Matsumura M., Moriwaki A., Kan-o K., Wada Y., Yagita H., Shin T., Pardoll D. M., Patcharee R., Azuma M., Nakanishi Y., Inoue H. B 7-DC induced by IL-13 works as a feedback regulator in the effector phase of allergic asthma. Biochem Biophys Res Commun. 2008, 365(1), 170-175.
  88. Matsumoto K., Inoue H., Nakano T., Tsuda M., Yoshiura Y., Fukuyama S., Tsushima F., Hoshino T., Aizawa H., Akiba H., Pardoll D., Hara N., Yagita H., Azuma M., Nakanishi Y. B 7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol. 2004, 172(4), 2530-2541.
  89. Lewkowich I. P., Lajoie S., Stoffers S. L., Suzuki Y., Richgels P. K., Dienger K., Sproles A. A., Yagita H., Hamid Q., Wills-Karp M. PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol. 2013. 6(4), 728-739.
  90. Delgoffe G. M., Pollizzi K. N., Waickman A. T., Heikamp E., Meyers D. J., Horton M. R., Xiao B., Worley P. F., Powell J. D. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC 1 and mTORC 2. Nat Immunol. 2011, 12, 295-303.
  91. Lee K., Gudapati P., Dragovic S., Spencer C., Joyce S., Killeen N., Magnuson M. A., Boothby M. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010, 32, 743-753.
  92. Powell J. D., Pollizzi K. N., Heikamp E. B., Horton M. R. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012, 30, 39-68.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2017 Toptygina A.P.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № 77 - 11525 от 04.01.2002.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies