PD-1 receptor blockade promotes clearance of a persistent viral Infection by overriding prolonged T cell engagement

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NINDS	IMMUNO/INFLAM-34

* FARE Award Winner

Authors

• BH Zinselmeyer
• S Heydari
• D Nayak
• DB McGavern

Abstract

The recent demonstration of improved anti-viral T cell function following PD-1 blockade is a finding of great clinical importance. Presently, it is not clear how the blockade of this inhibitory pathway improves the function of exhausted T cells. Infection of mice with an immunosuppressive strain of LCMV is a well described paradigm to study T cell exhaustion. In this study we sought insights into the mechanisms of T cell exhaustion during persistent infection by simultaneously imaging CD8 and CD4 T cell responses using two-photon microscopy in the spleen. To define the dynamics of immune exhaustion, we compared anti-viral T cell dynamics during an acute versus a persistent LCMV infection. Analyses of T cells revealed that exhaustion during viral persistence is associated with prolonged TCR signaling and cellular arrest in the splenic marginal zone and red pulp. Intravenous injection of anti-PD-1 enhanced splenic anti-viral T cell motility within 30 minutes, and this was followed hours later by elevated IFN-gamma production, reduced viral loads, and the onset of severe fatal disease. These data indicate that immune exhaustion is mediated in part by T cell motility paralysis and that PD-1 blockade improves viral clearance by decreasing the duration of cellular arrest.

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