Purpose of Review
Toxoplasmosis is an apicomplexan parasite that can be found in all countries, which causes an infection of the central nervous system. This review outlines some of the recent immunological advances that have been made against this chronic infection that poses a major problem for the immunocompromised individuals.
Recent studies have demonstrated that in a mouse model of chronic toxoplasmosis, the infection leads to T cell dysfunctionality. The exhaustion that is observed in both CD4 and CD8 T cells is manifested by increased expression of co-inhibitory molecules like PD-1 and leads to reactivation of latent infection. Blockade of PD-1-PDL-1 interaction reverses the exhaustion and prevents reactivation of latent infection in the host.
Prevention of loss of CD4 T cell function can be important therapeutic strategy for controlling chronic toxoplasmosis and preventing reactivation of latent infection.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance
Luft BJ, Castro KG. An overview of the problem of toxoplasmosis and pneumocystosis in AIDS in the USA: implication for future therapeutic trials. Eur J Clin Microbiol Infect Dis. 1991;10(3):178–81.
Clumeck N, Hermans P. New therapeutic approaches in the acquired immune deficiency syndrome. Antibiot Chemother (1971). 1991;43:235–56.
Zumla A, Savva D, Wheeler RB, Hira SK, Luo NP, Kaleebu P, et al. Toxoplasma serology in Zambian and Ugandan patients infected with the human immunodeficiency virus. Trans R Soc Trop Med Hyg. 1991;85(2):227–9.
Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965–76.
Bharti AR, McCutchan A, Deutsch R, Smith DM, Ellis RJ, Cherner M, et al. Latent toxoplasma infection and higher Toxoplasma gondii immunoglobulin G levels are associated with worse neurocognitive functioning in HIV-infected adults. Clin Infect Dis. 2016;63:1655–60.
Cuervo G, Simonetti AF, Alegre O, Sanchez-Salado JC, Podzamczer D. Toxoplasma myocarditis: a rare but serious complication in an HIV-infected late presenter. AIDS. 2016;30(14):2253–4.
Kravetz JD, Federman DG. Prevention of toxoplasmosis in pregnancy: knowledge of risk factors. Infect Dis Obstet Gynecol. 2005;13(3):161–5.
Gazzinelli RT, Mendonça-Neto R, Lilue J, Howard J, Sher A. Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe. 2014;15(2):132–8.
Sasai M, Pradipta A, Yamamoto M. Host immune responses to Toxoplasma gondii. Int Immunol. 2018;30(3):113–9.
Sasai M, Yamamoto M. Pathogen recognition receptors: ligands and signaling pathways by toll-like receptors. Int Rev Immunol. 2013;32(2):116–33.
Yarovinsky F. Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol. 2014;14(2):109–21.
Denkers EY, Butcher BA, del Rio L, Bennouna S. Neutrophils, dendritic cells and Toxoplasma. Int J Parasitol. 2004;34(3):411–21.
Shah S, Grotenbreg GM, Rivera A, Yap GS. An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12. Elife. 2015;4.
Liesenfeld O, Kosek J, Remington JS, Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med. 1996;184(2):597–607.
Hwang S, Khan IA. CD8+ T cell immunity in an encephalitis model of Toxoplasma gondii infection. Semin Immunopathol. 2015;37(3):271–9.
Khan IA, Smith KA, Kasper LH. Induction of antigen-specific parasiticidal cytotoxic T cell splenocytes by a major membrane protein (P30) of Toxoplasma gondii. J Immunol. 1988;141(10):3600–5.
Khan IA, Ely KH, Kasper LH. Antigen-specific CD8+ T cell clone protects against acute Toxoplasma gondii infection in mice. J Immunol. 1994;152(4):1856–60.
Gazzinelli RT, et al. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol. 1991;146(1):286–92.
Brown CR, McLeod R. Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection. J Immunol. 1990;145(10):3438–41.
Suzuki Y, Wang X, Jortner BS, Payne L, Ni Y, Michie SA, et al. Removal of Toxoplasma gondii cysts from the brain by perforin-mediated activity of CD8+ T cells. Am J Pathol. 2010;176(4):1607–13.
Feliu V, Vasseur V, Grover HS, Chu HH, Brown MJ, Wang J, et al. Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite. PLoS Pathog. 2013;9(6):e1003449.
Bhadra R, Cobb DA, Khan IA. Donor CD8+ T cells prevent Toxoplasma gondii de-encystation but fail to rescue the exhausted endogenous CD8+ T cell population. Infect Immun. 2013;81(9):3414–25.
Suzuki Y, Orellana M, Schreiber R, Remington J. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988;240(4851):516–8.
Denkers EY, et al. Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol. 1997;159(4):1903–8.
Bhadra R, Gigley JP, Khan IA. PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. J Infect Dis. 2012;206(1):125–34.
Xia D, Hao S, Xiang J. CD8+ cytotoxic T-APC stimulate central memory CD8+ T cell responses via acquired peptide-MHC class I complexes and CD80 costimulation, and IL-2 secretion. J Immunol. 2006;177(5):2976–84.
Brown CR, et al. Effects of human class I transgenes on Toxoplasma gondii cyst formation. J Immunol. 1994;152(9):4537–41.
Deckert-Schluter M, et al. Toxoplasma encephalitis in congenic B10 and BALB mice: impact of genetic factors on the immune response. Infect Immun. 1994;62(1):221–8.
Hiszczynska-Sawicka E, et al. Comparison of immune response in sheep immunized with DNA vaccine encoding Toxoplasma gondii GRA7 antigen in different adjuvant formulations. Exp Parasitol. 2010;124(4):365–72.
Beghetto E, Nielsen HV, del Porto P, Buffolano W, Guglietta S, Felici F, et al. A combination of antigenic regions of Toxoplasma gondii microneme proteins induces protective immunity against oral infection with parasite cysts. J Infect Dis. 2005;191(4):637–45.
Scorza T, D’Souza S, Laloup M, Dewit J, de Braekeleer J, Verschueren H, et al. A GRA1 DNA vaccine primes cytolytic CD8(+) T cells to control acute Toxoplasma gondii infection. Infect Immun. 2003;71(1):309–16.
Blanchard N, Gonzalez F, Schaeffer M, Joncker NT, Cheng T, Shastri AJ, et al. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum. Nat Immunol. 2008;9(8):937–44.
Wilson DC, Grotenbreg GM, Liu K, Zhao Y, Frickel EM, Gubbels MJ, et al. Differential regulation of effector- and central-memory responses to Toxoplasma gondii infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells. PLoS Pathog. 2010;6(3):e1000815.
Gazzinelli R, et al. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol. 1992;149(1):175–80.
Bhadra R, Gigley JP, Weiss LM, Khan IA. Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade. Proc Natl Acad Sci U S A. 2011;108(22):9196–201.
Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2009;106(21):8623–8.
Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol. 2007;19(4):408–15.
Green AM, Difazio R, Flynn JL. IFN-gamma from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol. 2013;190(1):270–7.
Williams MA, Holmes BJ, Sun JC, Bevan MJ. Developing and maintaining protective CD8+ memory T cells. Immunol Rev. 2006;211:146–53.
Carvalho LH, Sano GI, Hafalla JCR, Morrot A, de Lafaille MAC, Zavala F. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nat Med. 2002;8(2):166–70.
Casciotti L, Ely KH, Williams ME, Khan IA. CD8(+)-T-cell immunity against toxoplasma gondii can be induced but not maintained in mice lacking conventional CD4(+) T cells. Infect Immun. 2002;70(2):434–43.
Shearer GM, et al. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986;137(8):2514–21.
Gigley JP, Bhadra R, Moretto MM, Khan IA. T cell exhaustion in protozoan disease. Trends Parasitol. 2012;28(9):377–84.
• Hwang S, et al. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis. J Exp Med. 2016;213(9):1799–818 These studies for the first time reported BLIMP-1-mediated CD4 T cell exhaustion during chronic T. gondii infection.
• Moretto MM, Hwang S, Khan IA. Downregulated IL-21 response and T follicular helper cell exhaustion correlate with compromised CD8 T cell immunity during chronic toxoplasmosis. Front Immunol. 2017;8:1436 In these studies for the first time, exhaustion of FTH population during chronic infection was reported.
• Melssen M, Slingluff CL Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol. 2017;47:85–92 It has been emphasized that CD4 T cells play a critical helper role in the strategies involving cancer immunotherapy.
Bhadra R, Gigley JP, Khan IA. Cutting edge: CD40-CD40 ligand pathway plays a critical CD8-intrinsic and -extrinsic role during rescue of exhausted CD8 T cells. J Immunol. 2011;187(9):4421–5.
Phan-Lai V, Dang Y, Gad E, Childs J, Disis ML. The antitumor efficacy of IL2/IL21-cultured polyfunctional Neu-specific T cells is TNFalpha/IL17 dependent. Clin Cancer Res. 2016;22(9):2207–16.
Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009;31(2):309–20.
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.
Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34.
Miles B, Miller SM, Connick E. CD4 T follicular helper and regulatory cell dynamics and function in HIV infection. Front Immunol. 2016;7:659.
Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324(5934):1572–6.
This work was supported by the NIH grant AI33325 awarded to IAK.
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Parasitology
About this article
Cite this article
Khan, I.A., Ouellette, C., Chen, K. et al. Toxoplasma: Immunity and Pathogenesis. Curr Clin Micro Rpt 6, 44–50 (2019). https://doi.org/10.1007/s40588-019-0114-5
- CD8 T cells
- CD4 T cells