Dysfunctional γδ T cells: a contributing factor for clinical tolerance to malaria?

γδ T cells are a small subset of T cells that can rapidly recognize and respond to antigen in a non-MHC restricted manner. The importance of γδ T cells during malaria infection is established by studies in both mouse models and with human cells, where γδ T cells expand during acute blood stage infections (1,2) and control parasitemia (3). We and others have demonstrated that human γδ T cells are one of the predominant cytokine producers following stimulation with Plasmodium-infected red blood cells in vitro (4-6) and following infection (7,8). γδ T cell cytokine responses are also associated with severe disease (9).

Recently, Jagannathan et al. [2014] (10) described compositional modification and presence of dysfunctional γδ T cells in the periphery of individuals living in malaria hyper endemic areas of Uganda. The study cohort consisted of 78 HIV-uninfected children enrolled before 1 year of age. Routine blood smears were performed monthly on these children until the age of 5 years to obtain a comprehensive clinical record of asymptomatic and symptomatic episodes. Children with episodes of fever (tympanic temperature ≥38 °C) were assessed for malaria by thick blood smears and diagnosed malaria was treated with artemisinin-based combination therapy. The peripheral blood mononuclear cell (PBMC) samples used to investigate γδ T cells were collected at the age of 4 and 5.

The authors found that the incidence of symptomatic malaria for the cohort was 5.4 episodes per person-year (PPY) which declined with age whereas asymptomatic parasitemia increased. Assessment of γδ T cell subsets Vδ1 and Vδ2, uncovered a decrease in the frequency of Vδ2+ cells relative to prior incidence of malaria. Further investigation of Vδ2+ cells demonstrated a decline in functional capacity including proliferation and cytokine production in response to malaria-specific stimulation, and was negatively associated with increased prior malaria incidence. The authors subsequently investigated whether upregulation of immunoregulatory pathways was a result of repeated infection. Consequently comparison of basal gene expression and malaria antigen-induced gene expression was performed between children with <2 prior episodes PPY and children with ≥8 episodes. Basal gene expression identified a higher expression of immunomodulatory genes in highly exposed children whereas mRNA encoding for cytokines were significantly expressed at higher levels in children with <2 prior episodes PPY following stimulation. The frequency and function of Vδ2+ cells was subsequently analysed relative to clinical immunity. The authors found that the frequency of malaria-responsive Vδ2+ cells was significantly lower in children who experienced asymptomatic episode compared to children who developed clinical malaria. While lower frequency of cytokine production was associated with higher risk of parasitemia, this conferred lower risk of clinical symptoms in highly exposed children. The authors conclude that γδ T cells do not protect from infection, but with loss of responsive Vδ2+ cells there is an increased probability of asymptomatic infection.

This study clearly contributes to the current understanding of malaria immunology. The cohort offers good measures of exposure relative to clinical and immunological outcomes. The high rate of exposure (379 infective bites PPY in 2012) (11) and malaria incidence of the cohort is likely to resemble chronic infections with other pathogens (e.g., HIV or HCV) in which dysfunctional cells are a well-established occurrence (12). Thus the findings of dysfunctional γδ T cells in this cohort are consistent with previous reports of dysregulated cells and chronic immune activation. However, the high frequency of infections in the cohort also confers limitations as samples are not necessarily collected during convalescence and this may affect the ability to assess cell functionality and gene expression. In fact 22% of the children were parasitemic at the time of sample collection. Although the authors found no significant difference in the percentage of cytokine producing cells compared to non-parasitemic children, it would have been interesting to take “time lapsed from last infection” into account in the analysis. This would potentially allow separating effects from recent infection such as contraction phase from persistently existing atypical γδ T cell distribution and function. Although the study indicates that exposure is an important factor for the observations made, it will also be interesting to establish whether similar findings are observed in individuals living in areas of lower endemicity where clinical tolerance is also noted.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Ho M, Webster HK, Tongtawe P, et al. Increased gamma delta T cells in acute Plasmodium falciparum malaria. Immunol Lett 1990;25:139-41. [PubMed]
2. Langhorne J. The immune response to the blood stages of Plasmodium in animal models. Immunol Lett 1994;41:99-102. [PubMed]
3. Weidanz WP, LaFleur G, Brown A, et al. Gammadelta T cells but not NK cells are essential for cell-mediated immunity against Plasmodium chabaudi malaria. Infect Immun 2010;78:4331-40. [PubMed]
4. D'Ombrain MC, Hansen DS, Simpson KM, et al. gammadelta-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-gamma response to Plasmodium falciparum malaria. Eur J Immunol 2007;37:1864-73. [PubMed]
5. Goodier MR, Lundqvist C, Hammarström ML, et al. Cytokine profiles for human V gamma 9+ T cells stimulated by Plasmodium falciparum. Parasite Immunol 1995;17:413-23. [PubMed]
6. Hensmann M, Kwiatkowski D. Cellular basis of early cytokine response to Plasmodium falciparum. Infect Immun 2001;69:2364-71. [PubMed]
7. D'Ombrain MC, Robinson LJ, Stanisic DI, et al. Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin Infect Dis 2008;47:1380-7. [PubMed]
8. Teirlinck AC, McCall MB, Roestenberg M, et al. Longevity and composition of cellular immune responses following experimental Plasmodium falciparum malaria infection in humans. PLoS Pathog 2011;7:e1002389. [PubMed]
9. Stanisic DI, Cutts J, Eriksson E, et al. γδ T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria. J Infect Dis 2014;210:295-305. [PubMed]
10. Jagannathan P, Kim CC, Greenhouse B, et al. Loss and dysfunction of Vδ2 γδ T cells are associated with clinical tolerance to malaria. Sci Transl Med 2014;6:251ra117.
11. Jagannathan P, Muhindo MK, Kakuru A, et al. Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda. Malar J 2012;11:435. [PubMed]
12. Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol 2007;19:408-15. [PubMed]