Malawian children with uncomplicated and cerebral malaria have decreased activated Vγ9Vδ2 γδ T cells which increase in convalescence

Autoři: Visopo Harawa aff001;  Madi Njie aff004;  Thomas Keller aff005;  Kami Kim aff005;  Anthony Jaworowski aff006;  Karl Seydel aff003;  Stephen J. Rogerson aff004;  Wilson Mandala aff001
Působiště autorů: Biomedical Sciences Department, College of Medicine, University of Malawi, Blantyre, Malawi aff001;  Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi aff002;  Blantyre Malaria Project, Blantyre, Malawi aff003;  Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia aff004;  University of South Florida, Tampa, Florida, United States of America aff005;  Department of Infectious Diseases, Monash University, Melbourne, Australia aff006;  School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia aff007;  Michigan State University, East Lansing, Michigan, United States of America aff008;  Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi aff009
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Malaria is responsible for almost half a million deaths annually. The role of Vγ9Vδ2 γδ T cells in malaria is still unclear. Studies have reported an association between this cell subset and malaria symptoms and severity. Profiles of Vγ9Vδ2 γδ T cells in bigger cohorts with different levels of clinical severity have not been described. Proportion, numbers, and activation status of Vγ9Vδ2 γδ T cells were measured by flow cytometry in 59 healthy controls (HCs), 58 children with uncomplicated malaria (UM) and 67 with cerebral malaria (CM,) during acute malaria and in convalescence 28 days later. Vγ9Vδ2 γδ T cell were lower in children presenting with UM and CM than in HCs. Cell counts did not vary with malaria severity (CM median counts 40 x 103 cells/μL, IQR [23–103]; UM median counts 30 x 103 cells/μL [10–90], P = 0.224). Vγ9Vδ2 γδ T cell counts increased during convalescence for UM (70 [40–60] x 103 cells/μL and CM (90 [60–140] x 103 cells/μL), to levels similar to those in HCs (70 [50–140] x 103 cells/μL), p = 0.70 and p = 0.40 respectively. Expression of the activation markers CD69 and HLA-DR on Vγ9Vδ2 γδ T cells was higher in malaria cases than in controls (HCs vs UM or CM, p < 0.0001) but was similar between UM and CM. HLA-DR expression remained elevated at 28 days, suggesting sustained activation of Vγ9Vδ2 γδ T cells during recovery. Vγ9Vδ2 γδ T cell proportions and cells counts were suppressed in acute disease and normalized in convalescence, a phenomenon previously hypothesized to be due to transient migration of the cells to secondary lymphoid tissue. The presence of highly activated Vγ9Vδ2 γδ T cells suggests that this T cell subset plays a specific role in response to malaria infection.

Klíčová slova:

Immune response – Lymphocytes – Malaria – Malarial parasites – T cells – Cerebral malaria – Convalescence – Cell enumeration techniques


1. WHO Global Malaria Programme. World Malaria Report 2016. Geneva: World Health Organization; 2016

2. Jagannathan P, Kim CC, Greenhouse B, Nankya F, Bowen K, Feeney ME, et al. Loss and dysfunction of Vδ2+ γδ T cells are associated with clinical tolerance to malaria. 2014;117.

3. Vantourout P, Hayday A. Six-of-the-best: Unique contributions of γδ T cells to immunology. Nat Rev Immunol. 2013;13(2):88–100. doi: 10.1038/nri3384 23348415

4. Howard J, Loizon S, Tyler CJ, Duluc D, Moser B, Mechain M, et al. The Antigen-Presenting Potential of Vγ9Vδ 2 T Cells during Plasmodium falciparum Blood-Stage Infection. J Infect Dis. 2017;215(10):1569–79. doi: 10.1093/infdis/jix149 28368498

5. Daubenberger CA, Salomon M, Vecino W, Hubner B, Troll H, Rodriques R, et al. Functional and Structural Similarity of Vγ9Vδ2 T Cells in Humans and Aotus Monkeys, a Primate Infection Model for Plasmodium falciparum Malaria. J Immunol. 2001;167(11):6421–30. doi: 10.4049/jimmunol.167.11.6421 11714808

6. Schofield L, Ioannidis LJ, Karl S, Robinson LJ, Tan QY, Poole DP, et al. Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of γδ T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC Med. 2017;15(1):1–15. doi: 10.1186/s12916-016-0759-3

7. Deroost K, Langhorne J. Gamma/Delta T Cells and Their Role in Protection Against Malaria. Front Immunol. 2018;9(December):2973.

8. Jones SM, Goodier MR, Langhorne J. The response of gamma delta T cells to Plasmodium falciparum is dependent on activated CD4+ T cells and the recognition of MHC class I molecules. Immunology. 1996;89:405–12. doi: 10.1046/j.1365-2567.1996.d01-762.x 8958054

9. Rzepczyk CM, Anderson K, Stamatiou S, Townsend E, Allworth A, McCormack J, et al. γδ T cells: Their immunobiology and role in malaria infections. Int J Parasitol. 1997;27(2):191–200. doi: 10.1016/s0020-7519(96)00149-x 9088990

10. Stanisic DI, Cutts J, Eriksson E, Fowkes FJI, Rosanas-Urgell A, Siba P, et al. γδ T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria. J Infect Dis. 2014;210(2):295–305. doi: 10.1093/infdis/jiu083 24523513

11. Seixas EMG, Langhorne J. Gamma delta T cells contribute to control of chronic parasitemia in Plasmodium chabaudi infections in mice. J Immunol. 1999;162(5):2837–41. 10072531

12. McKenna KC, Tsuji M, Sarzotti M, Sacci JB, Witney AA, Azad AF. T cells are a component of early immunity against preerythrocytic malaria parasites. Infect Immun. 2000;68(4):2224–30. doi: 10.1128/iai.68.4.2224-2230.2000 10722623

13. Perera BMK, Carter R, Goonewardene R, Mendis KN. Transient Increase in Circulating γ/δ T Cells during Plasmodium vivax Malarial Paroxysms. J Exp. Med. 1994;179(January):311–5.

14. Ho M, Tongtawe P, Kriangkum J, Wimonwattrawatee T, Pattanapanyasat K, Bryant L, et al. Polyclonal expansion of peripheral gamma delta T cells in human Plasmodium falciparum malaria. Infect Immun. 1994;62(3):855–62. 8112855

15. Tsuji M, Mombaerts P, Lefrancois L, Nussenzweig RS, Zavala F, Tonegawa S. γδ T cells contribute to immunity against the liver stages of malaria in αβ T-cell-deficient mice. Proc Natl Acad Sci USA. 1994;91(1):345–9. doi: 10.1073/pnas.91.1.345 8278391

16. Eberl M, Moser B. Monocytes and γδ T cells: close encounters in microbial infection. Trends Immunol. 2009;30(12):562–8. doi: 10.1016/ 19853512

17. Haque A, Echchannaoui H, Seguin R, Schwartzman J, Kasper LH, Haque S. Cerebral malaria in mice: Interleukin-2 treatment induces accumulation of γδ T cells in the brain and alters resistant mice to susceptible-like phenotype. Am J Pathol. 2001;158(1):163–72. doi: 10.1016/s0002-9440(10)63954-5 11141489

18. Hviid L, Kurtzhals JA, Dodoo D, Rodrigues O, Rønn A, Commey JO, et al. The gamma/delta T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic. Infect Immun. 1996;64(10):4359–62. 8926112

19. Harawa V, Njie M, Kessler A, Choko A, Kumwenda B, Kampondeni S, et al. Brain swelling is independent of peripheral plasma cytokine levels in Malawian children with cerebral malaria. Malar J. 2018;17(1):1–11. doi: 10.1186/s12936-017-2149-5

20. Mandala WL, Msefula CL, Gondwe EN, Gilchrist JJ, Graham SM, Pensulo P, et al. Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria. Clin Vaccine Immunol. 2016;23(2):95–103.

21. Berg A, Patel S, Gonca M, David C, Otterdal K, Ueland T, et al. Cytokine network in adults with falciparum malaria and HIV-1: Increased IL-8 and IP-10 levels are associated with disease severity. PLoS One. 2014;9(12):1–16.

22. Finney CAM, Ayi K, Wasmuth JD, Sheth PM, Kaul R, Loutfy MR, et al. HIV infection deregulates innate immunity to malaria despite combination antiretroviral therapy. Aids. 2013;27(3):325–35. doi: 10.1097/QAD.0b013e32835b3dfa 23291537

23. Kessler A, Dankwa S, Bernabeu M, Seydel KB, Smith JD, Kim K, et al. Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell Host Microbe. 2017;1–14.

24. Kuhn M, Johnson K. Applied predictive modeling. Springer Science + business media New York 2013.

25. Jagannathan P, Lutwama F, Boyle MJ, Nankya F, Farrington LA, McIntyre TI, et al. Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci Rep. 2017;7(1):1–12. doi: 10.1038/s41598-016-0028-x

26. Schoenberger SP. CD69 guides CD4+ T cells to the seat of memory. Proc Natl Acad Sci. 2012;109(22):8358–9. doi: 10.1073/pnas.1204616109 22615400

27. Shinoda K, Tokoyoda K, Hanazawa A, Hayashizaki K, Zehentmeier S, Hosokawa H, et al. Type II membrane protein CD69 regulates the formation of resting T-helper memory. Proc Natl Acad Sci. 2012;109(19):7409–14. doi: 10.1073/pnas.1118539109 22474373

28. Lopez-cabrera BM, Santis AG, Fern E, Blacher R, Esch F, Francisco S. Molecular Cloning, expression and chromosal localization of the human earliest lymphocyte activation antigen AIM/CD69, a new member of the C-type animal lectin superfamily of signal transmitting receptors. J. Exp. Med. 1993;178(2):537–547. doi: 10.1084/jem.178.2.537 8340758

29. Craston R, Koh M, Mc Dermott A, Ray N, Prentice HG, Lowdell MW. Temporal dynamics of CD69 expression on lymphoid cells. J Immunol Methods. 1997;209(1):37–45. doi: 10.1016/s0022-1759(97)00143-9 9448032

30. Cebrian M, Yague E, Rincon M, Lopez-botet M, Landazuri M, Sanchez-madrid F, et al. Triggering of cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes; Human T lymphocytes can be activated by interaction with different stimuli, including antigens, mitogenic lectins, and antibodies. J. Exp. Med. 1988;168(5):1621–1637. doi: 10.1084/jem.168.5.1621 2903209

31. Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C, et al. Differentiation of effector/memory Vδ2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med. 2003;198(3):391–7. doi: 10.1084/jem.20030235 12900516

32. Worku S, Björkman A, Troye-Blomberg M, Jemaneh L, Färnert A, Christensson B. Lymphocyte activation and subset redistribution in the peripheral blood in acute malaria illness: distinct gammadelta+ T cell patterns in Plasmodium falciparum and P. vivax infections. Clin Exp Immunol. 1997;108:34–41. doi: 10.1046/j.1365-2249.1997.d01-981.x 9097908

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