CCR2 Inflammatory Dendritic Cells and Translocation of Antigen by Type III Secretion Are Required for the Exceptionally Large CD8 T Cell Response to the Protective YopE Epitope during Infection


Dendritic cells (DCs) direct host protective adaptive immune responses during infection. How different subpopulations of DCs contribute to the formation of antigen-specific CD8+ T cells is incompletely understood. Infection of C57BL/6 mice with the bacterial pathogen Yersinia pseudotuberculosis results in the production of an exceptionally large CD8+ T cell response to an epitope in the type III secretion system effector YopE. Here, we show that this large CD8+ T cell response requires translocation of YopE into inflammatory DCs, which express CCR2 and accumulate in infected tissues. In contrast, when mice are infected with a Y. pseudotuberculosis strain that can secrete but not translocate YopE, a smaller response is seen, and under these conditions the generation of YopE-specific CD8+ T cell requires CD8α+ DCs. Our results indicate that distinct DC subsets participate in constructing the CD8+ T cell response to secreted, versus translocated, YopE. Furthermore our data indicate that inflammatory DCs are a driving force behind the massive CD8+ T cell response to a protective epitope in a bacterial virulence factor that is translocated into host cells.


Vyšlo v časopise: CCR2 Inflammatory Dendritic Cells and Translocation of Antigen by Type III Secretion Are Required for the Exceptionally Large CD8 T Cell Response to the Protective YopE Epitope during Infection. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005167
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1005167

Souhrn

Dendritic cells (DCs) direct host protective adaptive immune responses during infection. How different subpopulations of DCs contribute to the formation of antigen-specific CD8+ T cells is incompletely understood. Infection of C57BL/6 mice with the bacterial pathogen Yersinia pseudotuberculosis results in the production of an exceptionally large CD8+ T cell response to an epitope in the type III secretion system effector YopE. Here, we show that this large CD8+ T cell response requires translocation of YopE into inflammatory DCs, which express CCR2 and accumulate in infected tissues. In contrast, when mice are infected with a Y. pseudotuberculosis strain that can secrete but not translocate YopE, a smaller response is seen, and under these conditions the generation of YopE-specific CD8+ T cell requires CD8α+ DCs. Our results indicate that distinct DC subsets participate in constructing the CD8+ T cell response to secreted, versus translocated, YopE. Furthermore our data indicate that inflammatory DCs are a driving force behind the massive CD8+ T cell response to a protective epitope in a bacterial virulence factor that is translocated into host cells.


Zdroje

1. Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, et al. (2002) In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17: 211–220. 12196292

2. Sigal LJ, Crotty S, Andino R, Rock KL (1999) Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. Nature 398: 77–80. 10078533

3. Gromme M, Neefjes J (2002) Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Mol Immunol 39: 181–202. 12200050

4. Joffre OP, Segura E, Savina A, Amigorena S (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12: 557–569. doi: 10.1038/nri3254 22790179

5. Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7: 19–30. 17170756

6. Metlay JP, Witmer-Pack MD, Agger R, Crowley MT, Lawless D, et al. (1990) The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med 171: 1753–1771. 2185332

7. Steinman RM (2008) Dendritic cells in vivo: a key target for a new vaccine science. Immunity 29: 319–324. doi: 10.1016/j.immuni.2008.08.001 18799140

8. Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, et al. (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 207: 823–836. doi: 10.1084/jem.20091627 20351058

9. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, et al. (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322: 1097–1100. doi: 10.1126/science.1164206 19008445

10. Segura E, Amigorena S (2013) Inflammatory dendritic cells in mice and humans. Trends Immunol 34: 440–445. doi: 10.1016/j.it.2013.06.001 23831267

11. Leon B, Lopez-Bravo M, Ardavin C (2007) Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26: 519–531. 17412618

12. Daley-Bauer LP, Wynn GM, Mocarski ES (2012) Cytomegalovirus impairs antiviral CD8+ T cell immunity by recruiting inflammatory monocytes. Immunity 37: 122–133. doi: 10.1016/j.immuni.2012.04.014 22840843

13. Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11: 762–774. doi: 10.1038/nri3070 21984070

14. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG (2003) TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19: 59–70. 12871639

15. Tam JW, Kullas AL, Mena P, Bliska JB, van der Velden AW (2014) CD11b+ Ly6Chi Ly6G- immature myeloid cells recruited in response to Salmonella enterica serovar Typhimurium infection exhibit protective and immunosuppressive properties. Infect Immun 82: 2606–2614. doi: 10.1128/IAI.01590-13 24711563

16. Cornelis GR (2006) The type III secretion injectisome. Nat Rev Microbiol 4: 811–825. 17041629

17. Starnbach MN, Bevan MJ (1994) Cells infected with Yersinia present an epitope to class I MHC-restricted CTL. J Immunol 153: 1603–1612. 8046234

18. Zhang Y, Mena P, Romanov G, Lin JS, Smiley ST, et al. (2012) A protective epitope in type III effector YopE is a major CD8 T cell antigen during primary infection with Yersinia pseudotuberculosis. Infect Immun 80: 206–214. doi: 10.1128/IAI.05971-11 22064714

19. White DW, MacNeil A, Busch DH, Pilip IM, Pamer EG, et al. (1999) Perforin-deficient CD8+ T cells: in vivo priming and antigen-specific immunity against Listeria monocytogenes. J Immunol 162: 980–988. 9916723

20. Busch DH, Pilip IM, Vijh S, Pamer EG (1998) Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8: 353–362. 9529152

21. Bergsbaken T, Bevan MJ (2015) Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8(+) T cells responding to infection. Nat Immunol 16: 406–414. doi: 10.1038/ni.3108 25706747

22. Lin JS, Szaba FM, Kummer LW, Chromy BA, Smiley ST (2011) Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague. J Immunol 187: 897–904. doi: 10.4049/jimmunol.1100174 21653834

23. Szaba FM, Kummer LW, Duso DK, Koroleva EP, Tumanov AV, et al. (2014) TNFalpha and IFNgamma but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection. PLoS Pathog 10: e1004142. doi: 10.1371/journal.ppat.1004142 24854422

24. Zhang Y, Mena P, Romanov G, Bliska JB (2014) Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection. Infect Immun 82: 3033–3044. doi: 10.1128/IAI.01687-14 24799630

25. Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402: 255–262. 10580495

26. Harmon DE, Murphy JL, Davis AJ, Mecsas J (2013) A mutant with aberrant extracellular LcrV-YscF interactions fails to form pores and translocate Yop effector proteins but retains the ability to trigger Yop secretion in response to host cell contact. J Bacteriol 195: 2244–2254. doi: 10.1128/JB.02011-12 23475976

27. Palmer LE, Pancetti AR, Greenberg S, Bliska JB (1999) YopJ of Yersinia spp. is sufficient to cause downregulation of multiple mitogen-activated protein kinases in eukaryotic cells. Infect Immun 67: 708–716. 9916081

28. Boyd AP, Lambermont I, Cornelis GR (2000) Competition between the Yops of Yersinia enterocolitica for delivery into eukaryotic cells: role of the SycE chaperone binding domain of YopE. J Bacteriol 182: 4811–4821. 10940022

29. Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7: 311–317. 16462739

30. Durand EA, Maldonado-Arocho FJ, Castillo C, Walsh RL, Mecsas J (2010) The presence of professional phagocytes dictates the number of host cells targeted for Yop translocation during infection. Cell Microbiol 12: 1064–1082. doi: 10.1111/j.1462-5822.2010.01451.x 20148898

31. Koberle M, Klein-Gunther A, Schutz M, Fritz M, Berchtold S, et al. (2009) Yersinia enterocolitica targets cells of the innate and adaptive immune system by injection of Yops in a mouse infection model. PLoS Pathog 5: e1000551. doi: 10.1371/journal.ppat.1000551 19680448

32. Zlokarnik G, Negulescu PA, Knapp TE, Mere L, Burres N, et al. (1998) Quantitation of transcription and clonal selection of single living cells with beta-lactamase as reporter. Science 279: 84–88. 9417030

33. Zhang Y, Bliska JB (2010) YopJ-promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin-18, gamma interferon, and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection. Infect Immun 78: 2329–2341. doi: 10.1128/IAI.00094-10 20231414

34. Hohl TM, Rivera A, Lipuma L, Gallegos A, Shi C, et al. (2009) Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6: 470–481. doi: 10.1016/j.chom.2009.10.007 19917501

35. Badovinac VP, Porter BB, Harty JT (2002) Programmed contraction of CD8(+) T cells after infection. Nat Immunol 3: 619–626. 12055624

36. Shi C, Hohl TM, Leiner I, Equinda MJ, Fan X, et al. (2011) Ly6G+ neutrophils are dispensable for defense against systemic Listeria monocytogenes infection. J Immunol 187: 5293–5298. doi: 10.4049/jimmunol.1101721 21976773

37. Ye Z, Uittenbogaard AM, Cohen DA, Kaplan AM, Ambati J, et al. (2011) Distinct CCR2(+) Gr1(+) cells control growth of the Yersinia pestis DeltayopM mutant in liver and spleen during systemic plague. Infect Immun 79: 674–687. doi: 10.1128/IAI.00808-10 21149593

38. Russmann H, Shams H, Poblete F, Fu Y, Galan JE, et al. (1998) Delivery of epitopes by the Salmonella type III secretion system for vaccine development. Science 281: 565–568. 9677200

39. Soudja SM, Ruiz AL, Marie JC, Lauvau G (2012) Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 37: 549–562. doi: 10.1016/j.immuni.2012.05.029 22940097

40. Bohn E, Sing A, Zumbihl R, Bielfeldt C, Okamura H, et al. (1998) IL-18 (IFN-gamma-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice. J Immunol 160: 299–307. 9551984

41. Hein J, Kempf VA, Diebold J, Bucheler N, Preger S, et al. (2000) Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica. Infect Immun 68: 1408–1417. 10678954

42. Kerschen EJ, Cohen DA, Kaplan AM, Straley SC (2004) The plague virulence protein YopM targets the innate immune response by causing a global depletion of NK cells. Infect Immun 72: 4589–4602. 15271919

43. Zhang Y, Bliska JB (2011) Mathematical relationship between cytokine concentrations and pathogen levels during infection. Cytokine 53: 158–162. doi: 10.1016/j.cyto.2010.09.008 21093285

44. Zhang Y, Murtha J, Roberts MA, Siegel RM, Bliska JB (2008) Type III secretion decreases bacterial and host survival following phagocytosis of Yersinia pseudotuberculosis by macrophages. Infect Immun 76: 4299–4310. doi: 10.1128/IAI.00183-08 18591234

45. Simonet M, Falkow S (1992) Invasin expression in Yersinia pseudotuberculosis. Infect Immun 60: 4414–4417. 1398952

46. Zhang Y, Romanov G, Bliska JB (2011) Type III secretion system-dependent translocation of ectopically-expressed Yop effectors into macrophages by intracellular Yersinia pseudotuberculosis. Infect Immun.

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