{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/27887"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/27887","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"Regulation of Anti-Viral Cd8+ T Cell Responses by the Pd-1 Pathway","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Odorizzi, Pamela"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["E. John Wherry"],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-01-01","date_published":"2015-01-01","updated_at":"2026-07-24T03:47:06Z","subjects":[],"languages":["en"],"rights":["Pamela Odorizzi"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/27887","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["E. 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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. 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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."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/27887"],"dc:language":["en"],"dc:rights":["Pamela Odorizzi"],"dc:title":["Regulation of Anti-Viral Cd8+ T Cell Responses by the Pd-1 Pathway"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:47:06Z"}