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

Nature Medicine volume 14, pages 542–550 (2008)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Center for Tropical and Emerging Global Diseases, Coverdell Center, 500 D.W. Brooks Drive, University of Georgia, Athens, 30602, Georgia, USA

    Juan M Bustamante, Lisa M Bixby & Rick L Tarleton

  2. Department of Cellular Biology, Coverdell Center, 500 D.W. Brooks Drive, University of Georgia, Athens, 30602, Georgia, USA

    Lisa M Bixby & Rick L Tarleton

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  1. Juan M Bustamante
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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.

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Correspondence to Rick L Tarleton.

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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

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