title: PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection.
abstract: We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8(+) T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ(+)/granzyme B(-) memory but not effector CD8(+) T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8(+) T-cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections.
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC DC20037, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Bhadra
authors.forename: Jason P
authors.initials: JP
authors.lastname: Gigley
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Khan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology* / Q000378:metabolism; D014123:Toxoplasmosis / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D053804:Granzymes