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  • Original Article
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Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites

Abstract

Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites. This protection is known to be mediated in part by antigen-specific memory CD8+ T cells, presumably those residing in the liver. We characterized and compared the transcriptional profile of parasite-specific memory CD8+ T cells residing in the liver and spleen after immunization of mice with irradiated sporozoites. Microarray-based expression analysis of these memory CD8+ T cells indicated that liver-resident memory cells display a distinct gene expression profile. We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling. Importantly, the malaria parasite-induced liver-resident CD8+ T cells display a transcriptional profile different to that described for CD8+ T cells following other microbial challenges.

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References

  1. Overstreet MG, Cockburn IA, Chen Y, Zavala F . Protective CD8+ T cells against Plasmodium liver stages: immunobiolog of an ‘unnatural’ immune response. Immunol Rev 2008; 225: 272–282.

    Article  CAS  Google Scholar 

  2. Romero P, Maryanski JL, Corradin G, Nussenzweig RS, Nussenzweig V, Zavala F . Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 1989; 341: 323–326.

    Article  CAS  Google Scholar 

  3. Chakravarty S, Cockburn IA, Kuk S, Overstreet MG, Sacci JB, Zavala F . CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nat Med 2007; 13: 1035–1041.

    Article  CAS  Google Scholar 

  4. Morrot A, Hafalla JCR, Cockburn IA, Carvalho LH, Zavala F . IL-4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites. J Exp Med 2005; 202: 551–560.

    Article  CAS  Google Scholar 

  5. Cockburn IA, Tse S-W, Radtke AJ, Srinivasan P, Chen Y-C, Sinnis P et al. Dendritic cells and hepatocytes use distinct pathways to process protective antigen from Plasmodium in vivo. PLoS Pathog 2011; 7: e1001318.

    Article  CAS  Google Scholar 

  6. Woodland DL, Kohlmeier JE . Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 2009; 9: 153–161.

    Article  CAS  Google Scholar 

  7. Masopust D, Vezys V, Wherry EJ, Barber DL, Ahmed R . Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol 2006; 176: 2079–2083.

    Article  CAS  Google Scholar 

  8. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN et al. Long-Lived epithelial immunity by tissue-resident memory T (TRM) Cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci USA 2012; 109: 7037–7042.

    Article  CAS  Google Scholar 

  9. Sano G, Hafalla JCR, Morrot A, Abe R, Lafaille JJ, Zavala F . Swift Development of protective effector functions in naive CD8+ T Cells against malaria liver stages. J Exp Med 2001; 194: 173–180.

    Article  CAS  Google Scholar 

  10. Hokeness KL, Deweerd ES, Munks MW, Lewis CA, Gladue RP, Salazar-Mather TP . CXCR3-dependent recruitment of antigen-specific t lymphocytes to the liver during murine cytomegalovirus infection. J Virol 2007; 81: 1241–1250.

    Article  CAS  Google Scholar 

  11. Sato T, Thorlacius H, Johnston B, Staton TL, Xiang W, Littman DR et al. Role for CXCR6 in Recruitment of activated CD8+ Lymphocytes to inflamed liver. J Immunol 2005; 174: 277–283.

    Article  CAS  Google Scholar 

  12. Sarkar S, Kalia V, Haining WN, Konieczny BT, Subramaniam S, Ahmed R . Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J Exp Med 2008; 205: 625–640.

    Article  CAS  Google Scholar 

  13. Cao Z, Sun X, Icli B, Wara AK, Feinberg MW . Role of Krüppel-like factors in leukocyte development, function, and disease. Blood 2010; 116: 4404–4414.

    Article  CAS  Google Scholar 

  14. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007; 316: 295–298.

    Article  CAS  Google Scholar 

  15. Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP et al. Control of effector CD8+ T cell function by the transcription factor eomesodermin. Science 2003; 302: 1041–1043.

    Article  CAS  Google Scholar 

  16. Barbu EA, Zhang J, Berenstein EH, Groves JR, Parks LM, Siraganian RP . The Transcription factor Zeb2 Regulates signaling in mast cells. J Immunol 2012; 188: 6278–6286.

    Article  CAS  Google Scholar 

  17. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  18. Haining WN, Wherry EJ . Integrating genomic signatures for immunologic discovery. Immunity 2010; 32: 152–161.

    Article  CAS  Google Scholar 

  19. Kaech SM, Hemby S, Kersh E, Ahmed R . Molecular and Functional profiling of memory CD8 T Cell differentiation. Cell 2002; 111: 837–851.

    Article  CAS  Google Scholar 

  20. Cockburn IA, Chen Y-C, Overstreet MG, Lees JR, Van Rooijen N, Farber DL et al. Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites. PLoS Pathog 2010; 6: e1000877.

    Article  Google Scholar 

  21. Wirth TC, Xue H-H, Rai D, Sabel JT, Bair T, Harty JT et al. Repetitive Antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 2010; 33: 128–140.

    Article  CAS  Google Scholar 

  22. Wherry EJ, Ha S-J, Kaech SM, Haining WN, Sarkar S, Kalia V et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007; 27: 670–684.

    Article  CAS  Google Scholar 

  23. Gu X, Laouar A, Wan J, Daheshia M, Lieberman J, Yokoyama WM et al. The gp49B1 inhibitory receptor regulates the IFN-γ responses of T cells and NK cells. J Immunol 2003; 170: 4095–4101.

    Article  CAS  Google Scholar 

  24. Masopust D, Vezys V, Marzo AL, Lefrançois L . Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291: 2413–2417.

    Article  CAS  Google Scholar 

  25. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J et al. Inflammation Directs memory precursor and short-lived effector CD8(+) T Cell fates via the graded expression of T-bet transcription factor. Immunity 2007; 27: 281–295.

    Article  CAS  Google Scholar 

  26. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74: 185–195.

    Article  CAS  Google Scholar 

  27. Reiss Y, Proudfoot AE, Power CA, Campbell JJ, Butcher EC . CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J Exp Med 2001; 194: 1541–1547.

    Article  CAS  Google Scholar 

  28. Wakim LM, Woodward-Davis A, Bevan MJ, Memory T . Cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc Natl Acad Sci USA 2010; 107: 17872–17879.

    Article  CAS  Google Scholar 

  29. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR . Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 2009; 10: 524–530.

    Article  CAS  Google Scholar 

  30. Masopust D, Choo D, Vezys V, Wherry EJ, Duraiswamy J, Akondy R et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J Exp Med 2010; 207: 553–564.

    Article  CAS  Google Scholar 

  31. Weinreich MA, Takada K, Skon C, Reiner SL, Jameson SC, Hogquist KA . KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 2009; 31: 122–130.

    Article  CAS  Google Scholar 

  32. Parish IA, Kaech SM . Diversity in CD8(+) T cell differentiation. Curr Opin Immunol 2009; 21: 291–297.

    Article  CAS  Google Scholar 

  33. Sebzda E, Zou Z, Lee JS, Wang T, Kahn ML . Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol 2008; 9: 292–300.

    Article  CAS  Google Scholar 

  34. Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP . The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 2000; 174: 47–62.

    Article  CAS  Google Scholar 

  35. Crispe IN . The Liver as a lymphoid organ. Annu Rev Immunol 2009; 27: 147–163.

    Article  CAS  Google Scholar 

  36. Wakim LM, Woodward-Davis A, Liu R, Hu Y, Villadangos J, Smyth G et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J Immunol 2012; 189: 3462–3471.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Alan Aderem, Stephen Ramsey and Michael Overstreet for insightful discussions, and Anne Jedlicka and the JHSPH Genomic Analysis and Sequencing Core for technical assistance. This work is supported by NIH grant number AI44375 (FZ). We also thank the Bloomberg Family Foundation for continued support. S Tse was supported by a pre-doctoral fellowship from the Johns Hopkins Malaria Research Institute.

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Correspondence to F Zavala.

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Tse, SW., Cockburn, I., Zhang, H. et al. Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites. Genes Immun 14, 302–309 (2013). https://doi.org/10.1038/gene.2013.20

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