Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

E. John Wherry

Abstract

PD-1 and its ligands, PD-L1 and PD-L2, constitute a critical immunoregulatory pathway for modulating CD8+ T cell responses. This pathway has become an important therapeutic target in cancer and chronic viral infections, where blockade of PD-1/PD-L1 reverses CD8+ T cell exhaustion and improves outcomes. However, it remains unclear how PD-1 pathway signals shape the development and maintenance of memory CD8+ T cell responses following acutely-resolved infection or exhausted CD8+ T cell responses following chronic infection. Absence of PD-1 results in early over-activation, excessive proliferation and diminished survival of virus-specific CD8+ T cells during both acutely-resolved and chronic viral infections. Following influenza infection, PD-1 pathway deficiency led to sub-optimal CD8+ T cell memory development. Defects were observed in the magnitude of the influenza-specific CD8+ T cell responses, as well as in cytokine production and recall capacity. Similarly, during chronic LCMV infection, PD-1 deficient CD8+ T cells were more dysfunctional than their WT counterparts. Permanent absence of PD-1 dramatically dysregulated lineage dynamics and long-term stability of exhausted CD8+ T cell populations through a mechanism involving the transcription factors T-bet and Eomesodermin. As a result, PD-1 deficiency led to the accumulation of terminally-differentiated, but more cytotoxic, exhausted CD8+ T cells. These findings reveal a novel dual role for PD-1 signals during acutely-resolved and chronic viral infections. PD-1 pathway signals clearly restrict CD8+ T cell activation, expansion and function early, consistent with previous work. However, in doing this, PD-1 also preserves the quantity and quality of long-term memory or exhausted CD8+ T cell responses. Thus, PD-1 acts as a critical "rheostat" on CD8+ T cells, balancing the need for activation to achieve pathogen clearance with the establishment and maintenance of long-term memory or exhausted T cell responses.

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