Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion.
The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8(+) T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations, such as the bone marrow, favored the survival of PD-1(Hi) exhausted CD8 T cells, suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of the anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway.
Blackburn
Shawn D
SD
Department of Medical Oncology, Dana Farber Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Crawford
Alison
A
Shin
Haina
H
Polley
Antonio
A
Freeman
Gordon J
GJ
Wherry
E John
EJ
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002470:Cell Survival; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010455:Peptides / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014779:Virus Replication
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor