J Infect Dis. 2012 Apr 26. [Epub ahead of print]
PD-1 mediated attrition of polyfunctional memory CD8+ T cells in chronic Toxoplasma infection
Bhadra R, Gigley JP, Khan IA.
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA.
We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 up-regulation, 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 PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and IFNγ(+)GranzymeB(-) 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.
PMID: 22539813 [PubMed - as supplied by publisher]