Malaria drives T cells to exhaustion

Michelle N Wykes, Joshua M Horne-Debets, Chiuan-Yee Leow, Deshapriya S Karunarathne, Michelle N Wykes, Joshua M Horne-Debets, Chiuan-Yee Leow, Deshapriya S Karunarathne

Abstract

Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp. Recent research on malaria, has investigated the programmed cell death-1 (PD-1) pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4(+) T cells and an unappreciated role for CD8(+) T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.

Keywords: B cells; CD4+ T cells; CD8+ T cell; PD-1; PD-L1; chronic disease; exhaustion; malaria.

References

    1. Agata Y., Kawasaki A., Nishimura H., Ishida Y., Tsubata T., Yagita H., et al. (1996). Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8 765–772 10.1093/intimm/8.5.765
    1. Alonso P. L., Sacarlal J., Aponte J. J., Leach A., Macete E., Aide P., et al. (2005). Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366 2012–2018 10.1016/S0140-6736(05)67669-6
    1. Beattie L., Engwerda C. R., Wykes M., Good M. F. (2006). CD8+ T lymphocyte-mediated loss of marginal metallophilic macrophages following infection with Plasmodium chabaudi chabaudi AS. J. Immunol. 177 2518–2526 10.4049/jimmunol.177.4.2518
    1. Bhadra R., Gigley J. P., Weiss L. M., Khan I. A. (2011). 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. 108 9196–9201 10.1073/pnas.1015298108
    1. Butler N. S., Moebius J., Pewe L. L., Traore B., Doumbo O. K., Tygrett L. T., et al. (2012). Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13 188–195 10.1038/ni.2180
    1. Butte M. J., Keir M. E., Phamduy T. B., Sharpe A. H., Freeman G. J. (2007). Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27 111–122 10.1016/j.immuni.2007.05.016
    1. Chandele A., Mukerjee P., Das G., Ahmed R., Chauhan V. S. (2011). Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii. Immunology 132 273–286 10.1111/j.1365-2567.2010.03363.x
    1. Chemnitz J. M., Parry R. V., Nichols K. E., June C. H., Riley J. L. (2004). SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173 945–954 10.4049/jimmunol.173.2.945
    1. Cohen S., McGregor I., Carrington S. (1961). Gamma-globulin and acquired immunity to human malaria. Nature 192 733–737 10.1038/192733a0
    1. Couper K. N., Blount D. G., Wilson M. S., Hafalla J. C., Belkaid Y., Kamanaka M., et al. (2008). IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog. 4:e1000004 10.1371/journal.ppat.1000004
    1. Crompton P. D., Kayala M. A., Traore B., Kayentao K., Ongoiba A., Weiss G. E., et al. (2010). A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray. Proc. Natl. Acad. Sci. U.S.A. 107 6958–6963 10.1073/pnas.1001323107
    1. Crotty S. (2011). Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29 621–663 10.1146/annurev-immunol-031210-101400
    1. Day C. L., Kaufmann D. E., Kiepiela P., Brown J. A., Moodley E. S., Reddy S., et al. (2006). PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 350–354 10.1038/nature05115
    1. Dong H., Zhu G., Tamada K., Chen L. (1999). B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5 1365–1369 10.1038/70932
    1. Freeman G. J., Long A. J., Iwai Y., Bourque K., Chernova T., Nishimura H., et al. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192 1027–1034 10.1084/jem.192.7.1027
    1. Freeman G. J., Wherry E. J., Ahmed R., Sharpe A. H. (2006). Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203 2223–2227 10.1084/jem.20061800
    1. Hafalla J. C., Claser C., Couper K. N., Grau G. E., Renia L., de Souza J. B., et al. (2012). The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology. PLoS Pathog. 8:e1002504 10.1371/journal.ppat.1002504
    1. Hafalla J. C., Cockburn I. A., Zavala F. (2006). Protective and pathogenic roles of CD8+ T cells during malaria infection. Parasite Immunol. 28 15–24 10.1111/j.1365-3024.2006.00777.x
    1. Hirunpetcharat C., Good M. F. (1998). Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite. Proc. Natl. Acad. Sci. U.S.A. 95 1715–1720 10.1073/pnas.95.4.1715
    1. Horne-Debets J. M., Faleiro R., Karunarathne D. S., Liu X. Q., Lineburg K. E., Poh C. M., et al. (2013). PD-1 dependent exhaustion of CD8(+) T cells drives chronic malaria. Cell Rep. 5 1204–1213 10.1016/j.celrep.2013.11.002
    1. Illingworth J., Butler N. S., Roetynck S., Mwacharo J., Pierce S. K., Bejon P., et al. (2013). Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J. Immunol. 190 1038–1047 10.4049/jimmunol.1202438
    1. Imai T., Ishida H., Suzue K., Hirai M., Taniguchi T., Okada H., et al. (2013). CD8(+) T cell activation by murine erythroblasts infected with malaria parasites. Sci. Rep. 3:1572 10.1038/srep01572
    1. Imai T., Shen J., Chou B., Duan X., Tu L., Tetsutani K., et al. (2010). Involvement of CD8+ T cells in protective immunity against murine blood-stage infection with Plasmodium yoelii 17XL strain. Eur. J. Immunol. 40 1053–1061 10.1002/eji.200939525
    1. Iwai Y., Terawaki S., Ikegawa M., Okazaki T., Honjo T. (2003). PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198 39–50 10.1084/jem.20022235
    1. Jacobs P., Radzioch D., Stevenson M. M. (1996). A Th1-associated increase in tumor necrosis factor alpha expression in the spleen correlates with resistance to blood-stage malaria in mice. Infect. Immun. 64 535–541
    1. Joshi T., Rodriguez S., Perovic V., Cockburn I. A., Stager S. (2009). B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog. 5:e1000431 10.1371/journal.ppat.1000431
    1. Keir M. E., Butte M. J., Freeman G. J., Sharpe A. H. (2008). PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26 677–704 10.1146/annurev.immunol.26.021607.090331
    1. Kisielow M., Kisielow J., Capoferri-Sollami G., Karjalainen K. (2005). Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur. J. Immunol. 35 2081–2088 10.1002/eji.200526090
    1. Langhorne J., Ndungu F. M., Sponaas A. M., Marsh K. (2008). Immunity to malaria: more questions than answers. Nat. Immunol. 9 725–732 10.1038/ni.f.205
    1. Latchman Y., Wood C. R., Chernova T., Chaudhary D., Borde M., Chernova I., et al. (2001). PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2 261–268 10.1038/85330
    1. Liang S. C., Greenwald R. J., Latchman Y. E., Rosas L., Satoskar A., Freeman G. J., et al. (2006). PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur. J. Immunol. 36 58–64 10.1002/eji.200535458
    1. Linterman M. A., Pierson W., Lee S. K., Kallies A., Kawamoto S., Rayner T. F., et al. (2011). Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17 975–982 10.1038/nm.2425
    1. Liu X. Q., Stacey K. J., Horne-Debets J. M., Cridland J. A., Fischer K., Narum D., et al. (2012). Malaria infection alters the expression of B-cell activating factor resulting in diminished memory antibody responses and survival. Eur. J. Immunol. 42 3291–3301 10.1002/eji.201242689
    1. Lukens J. R., Cruise M. W., Lassen M. G., Hahn Y. S. (2008). Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J. Immunol. 180 4875–4884 10.4049/jimmunol.180.7.4875
    1. McCall M. B., Hopman J., Daou M., Maiga B., Dara V., Ploemen I., et al. (2010). Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali. J. Infect. Dis. 201 142–152 10.1086/648596
    1. McCall M. B., Sauerwein R. W. (2010). Interferon-gamma–central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria. J. Leukoc. Biol. 88 1131–1143 10.1189/jlb.0310137
    1. Minigo G., Woodberry T., Piera K. A., Salwati E., Tjitra E., Kenangalem E., et al. (2009). Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog. 5:e1000402 10.1371/journal.ppat.1000402
    1. Muxel S. M., Freitas do Rosario A. P., Zago C. A., Castillo-Mendez S. I., Sardinha L. R., Rodriguez-Malaga S. M., et al. (2011). The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties. PLoS ONE 6:e22434 10.1371/journal.pone.0022434
    1. Ogutu B. R., Apollo O. J., McKinney D., Okoth W., Siangla J., Dubovsky F., et al. (2009). Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya. PLoS ONE 4:e4708 10.1371/journal.pone.0004708
    1. Olotu A., Fegan G., Wambua J., Nyangweso G., Awuondo K. O., Leach A., et al. (2013). Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N. Engl. J. Med. 368 1111–1120 10.1056/NEJMoa1207564
    1. Podoba J. E., Stevenson M. M. (1991). CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS. Infect. Immun. 59 51–58
    1. Scholzen A., Sauerwein R. W. (2013). How malaria modulates memory: activation and dysregulation of B cells in Plasmodium infection. Trends Parasitol. 29 252–262 10.1016/j.pt.2013.03.002
    1. Schwartz L., Brown G. V., Genton B., Moorthy V. S. (2012) A review of malaria vaccine clinical projects based on the WHO rainbow table. Malar. J. 11 11 10.1186/1475-2875-11-11
    1. Sharpe A. H., Wherry E. J., Ahmed R., Freeman G. J. (2007). The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8 239–245 10.1038/ni1443
    1. Stephens R., Langhorne J. (2010). Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria. PLoS Pathog. 6:e1001208 10.1371/journal.ppat.1001208
    1. Tran T. M., Li S., Doumbo S., Doumtabe D., Huang C. Y., Dia S., et al. (2013). An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin. Infect. Dis. 57 40–47 10.1093/cid/cit174
    1. Tseng S. Y., Otsuji M., Gorski K., Huang X., Slansky J. E., Pai S. I., et al. (2001). B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193 839–846 10.1084/jem.193.7.839
    1. Urbani S., Amadei B., Tola D., Massari M., Schivazappa S., Missale G., et al. (2006). PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80 11398–11403 10.1128/JVI.01177-06
    1. Urbani S., Amadei B., Tola D., Pedrazzi G., Sacchelli L., Cavallo M. C., et al. (2008). Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J. Hepatol. 48 548–558 10.1016/j.jhep.2007.12.014
    1. von der Weid T., Honarvar N., Langhorne J. (1996). Gene-targeted mice lacking B cells are unable to eliminate a blood stage malaria infection. J. Immunol. 156 2510–2516
    1. Walther M., Tongren J. E., Andrews L., Korbel D., King E., Fletcher H., et al. (2005). Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23 287–296 10.1016/j.immuni.2005.08.006
    1. Weiss G. E., Traore B., Kayentao K., Ongoiba A., Doumbo S., Doumtabe D., et al. (2010). The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. 6:e1000912 10.1371/journal.ppat.1000912
    1. Wherry E. J. (2011). T cell exhaustion. Nat. Immunol. 12 492–499 10.1038/ni.2035
    1. Wipasa J., Xu H., Stowers A., Good M. F. (2001). Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection. J. Immunol. 167 3903–3909 10.4049/jimmunol.167.7.3903
    1. Wykes M. N., Zhou Y. H., Liu X. Q., Good M. F. (2005). Plasmodium yoelii can ablate vaccine-induced long-term protection in mice. J. Immunol. 175 2510–2516 10.4049/jimmunol.175.4.2510
    1. Xu H., Wipasa J., Yan H., Zeng M., Makobongo M. O., Finkelman F. D., et al. (2002). The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection. J. Exp. Med. 195 881–892 10.1084/jem.20011174

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