Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease

Abstract

In this study, we document the development of stable, antigen-independent CD8+ T cell memory after drug-induced cure of a chronic infection. By establishing a system for drug cure of chronic Trypanosoma cruzi infection, we present the first extensively documented case of total parasite clearance after drug treatment of this infection. Cure resulted in the emergence of a stable, parasite-specific CD8+ T cell population with the characteristics of central memory cells, based upon expression of CD62L, CCR7, CD127, CD122, Bcl-2 and a reduced immediate in vivo CTL function. CD8+ T cells from treated and cured mice also expanded more rapidly and provided greater protection following challenge than those from chronically infected mice. These results show that complete pathogen clearance results in stable, antigen-independent and protective T cell memory, despite the potentially exhausting effects of prior long-term exposure to antigen in this chronic infection.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Benznidazole treatment results in parasitological cure in chronic T. cruzi infection.
Figure 2: Chronic phase cure results in conversion of parasite-specific CD8+ T cells to a TCM phenotype.
Figure 3: CD8+ T cells from treated and cured mice undergo homeostatic proliferation and maintain the ability to carry out effector functions.
Figure 4: TCM cells in treated and cured mice show strong antigen-induced proliferation after infection.
Figure 5: CD8+ T cells from treated and cured mice provide greater protection from challenge infection.
Figure 6: Benznidazole treatment in the late chronic phase of T. cruzi infection provides cure and conversion of T. cruzi–specific CD8+ T cells to a TCM phenotype.

References

  1. Grayson, J.M., Zajac, A.J., Altman, J.D. & Ahmed, R. Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    Article  CAS  Google Scholar 

  2. Wherry, E.J., Barber, D.L., Kaech, S.M., Blattman, J.N. & Ahmed, R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA 101, 16004–16009 (2004).

    Article  CAS  Google Scholar 

  3. Boyman, O., Purton, J.F., Surh, C.D. & Sprent, J. Cytokines and T-cell homeostasis. Curr. Opin. Immunol. 19, 320–326 (2007).

    Article  CAS  Google Scholar 

  4. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  5. Jameson, S.C. Maintaining the norm: T-cell homeostasis. Nat. Rev. Immunol. 2, 547–556 (2002).

    Article  CAS  Google Scholar 

  6. Becker, T.C. et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).

    Article  CAS  Google Scholar 

  7. Goldrath, A.W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).

    Article  CAS  Google Scholar 

  8. Zaph, C., Uzonna, J., Beverley, S.M. & Scott, P. Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites. Nat. Med. 10, 1104–1110 (2004).

    Article  CAS  Google Scholar 

  9. Cush, S.S., Anderson, K.M., Ravneberg, D.H., Weslow-Schmidt, J.L. & Flano, E. Memory generation and maintenance of CD8+ T cell function during viral persistence. J. Immunol. 179, 141–153 (2007).

    Article  CAS  Google Scholar 

  10. Bengsch, B. et al. Analysis of CD127 and KLRG1 expression on hepatitis C virus–specific CD8+ T cells reveals the existence of different memory T-cell subsets in the peripheral blood and liver. J. Virol. 81, 945–953 (2007).

    Article  CAS  Google Scholar 

  11. Shin, H., Blackburn, S.D., Blattman, J.N. & Wherry, E.J. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941–949 (2007).

    Article  CAS  Google Scholar 

  12. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  Google Scholar 

  13. Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  Google Scholar 

  14. Rehermann, B. Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Semin. Liver Dis. 27, 152–160 (2007).

    Article  CAS  Google Scholar 

  15. Shin, H. & Wherry, E.J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408–415 (2007).

    Article  CAS  Google Scholar 

  16. Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).

    Article  CAS  Google Scholar 

  17. Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461–2472 (2006).

    Article  CAS  Google Scholar 

  18. Vezys, V. et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 203, 2263–2269 (2006).

    Article  CAS  Google Scholar 

  19. Prata, A. Clinical and epidemiological aspects of Chagas disease. Lancet Infect. Dis. 1, 92–100 (2001).

    Article  CAS  Google Scholar 

  20. WHO Expert Committee. Control of Chagas disease. (WHO Technical Report Series 905) 120 (World Health Organization, Geneva, 2002).

  21. Tarleton, R.L. Depletion of CD8+ T cells increases susceptibility and reverses vaccine-induced immunity in mice infected with Trypanosoma cruzi. J. Immunol. 144, 717–724 (1990).

    CAS  PubMed  Google Scholar 

  22. Tarleton, R.L., Koller, B.H., Latour, A. & Postan, M. Susceptibility of β2-microglobulin–deficient mice to Trypanosoma cruzi infection. Nature 356, 338–340 (1992).

    Article  CAS  Google Scholar 

  23. Tarleton, R.L., Sun, J., Zhang, L. & Postan, M. Depletion of T-cell subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas disease. Infect. Immun. 62, 1820–1829 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin, D.L. & Tarleton, R.L. Antigen-specific T cells maintain an effector memory phenotype during persistent Trypanosoma cruzi infection. J. Immunol. 174, 1594–1601 (2005).

    Article  CAS  Google Scholar 

  25. Martin, D.L. et al. CD8+ T-cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. PLoS Pathog. 2, e77 (2006).

    Article  Google Scholar 

  26. Laucella, S.A. et al. Frequency of interferon-γ–producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease. J. Infect. Dis. 189, 909–918 (2004).

    Article  CAS  Google Scholar 

  27. Albareda, M.C. et al. Trypanosoma cruzi modulates the profile of memory CD8+ T cells in chronic Chagas' disease patients. Int. Immunol. 18, 465–471 (2006).

    Article  CAS  Google Scholar 

  28. Rodriques Coura, J. & de Castro, S.L. A critical review on Chagas disease chemotherapy. Mem. Inst. Oswaldo Cruz 97, 3–24 (2002).

    Article  Google Scholar 

  29. Zajac, A.J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    Article  CAS  Google Scholar 

  30. Zhang, J.-Y. et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 109, 4671–4678 (2007).

    Article  CAS  Google Scholar 

  31. Penna, A. et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45, 588–601 (2007).

    Article  CAS  Google Scholar 

  32. Zhang, L. & Tarleton, R.L. Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. J. Infect. Dis. 180, 480–486 (1999).

    Article  CAS  Google Scholar 

  33. Dutton, R.W., Bradley, L.M. & Swain, S.L. T cell memory. Annu. Rev. Immunol. 16, 201–223 (1998).

    Article  CAS  Google Scholar 

  34. Voehringer, D., Koschella, M. & Pircher, H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100, 3698–3702 (2002).

    Article  CAS  Google Scholar 

  35. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    Article  CAS  Google Scholar 

  36. Gallimore, A., Dumrese, T., Hengartner, H., Zinkernagel, R.M. & Rammensee, H.G. Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides. J. Exp. Med. 187, 1647–1657 (1998).

    Article  CAS  Google Scholar 

  37. Jabbari, A. & Harty, J.T. Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype. J. Exp. Med. 203, 919–932 (2006).

    Article  CAS  Google Scholar 

  38. Wherry, E.J., Blattman, J.N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911–4927 (2003).

    Article  CAS  Google Scholar 

  39. Sevilla, N. et al. Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J. Exp. Med. 192, 1249–1260 (2000).

    Article  CAS  Google Scholar 

  40. Yao, Z.Q., King, E., Prayther, D., Yin, D. & Moorman, J. T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. Viral Immunol. 20, 276–287 (2007).

    Article  CAS  Google Scholar 

  41. Seder, R.A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat. Immunol. 4, 835–842 (2003).

    Article  CAS  Google Scholar 

  42. Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat. Med. 7, 913–919 (2001).

    Article  CAS  Google Scholar 

  43. Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M. & Sacks, D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    Article  CAS  Google Scholar 

  44. Urbina, J.A. et al. Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. Int. J. Antimicrob. Agents 21, 39–48 (2003).

    Article  CAS  Google Scholar 

  45. Romanha, A.J. et al. Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-γ in mediating parasitologic cure. J. Infect. Dis. 186, 823–828 (2002).

    Article  CAS  Google Scholar 

  46. Engel, J.C., Doyle, P.S., Hsieh, I. & McKerrow, J.H. Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection. J. Exp. Med. 188, 725–734 (1998).

    Article  CAS  Google Scholar 

  47. Viotti, R., Vigliano, C., Armenti, H. & Segura, E. Treatment of chronic Chagas' disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up. Am. Heart J. 127, 151–162 (1994).

    Article  CAS  Google Scholar 

  48. Cancado, J.R. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev. Inst. Med. Trop. Sao Paulo 44, 29–37 (2002).

    Article  Google Scholar 

  49. Cummings, K.L. & Tarleton, R.L. Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Mol. Biochem. Parasitol. 129, 53–59 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Nelson of the Center for Tropical and Emerging Global Diseases Flow Cytometry Facility at the University of Georgia for technical assistance, C. Boehlke and G. Cooley for assistance with the parasites, M. Collins for critical reading of the manuscript, V. Alvarez and J. Cola Fernandes Rodrigues for assistance with the figures, and the Tetramer Core Facility (Emory University) for synthesis of MHC class I tetramers. The ELC-immunoglobulin chimera was a gift from K. Klonowski (University of Georgia). This work was supported by US National Institutes of Health grants AI-22070 and AI-33106 to R.L.T.

Author information

Authors and Affiliations

Authors

Contributions

J.M.B. designed and performed experiments and wrote the manuscript, L.M.B. performed experiments and assisted in writing of the manuscript and R.L.T. designed experiments and wrote the manuscript.

Corresponding author

Correspondence to Rick L Tarleton.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1 and 2 (PDF 72 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bustamante, J., Bixby, L. & Tarleton, R. Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nat Med 14, 542–550 (2008). https://doi.org/10.1038/nm1744

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1744

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing