Responsiveness of HIV-specific CD4 T cells to PD-1 blockade

• Published in: Blood Vol. 118; no. 4; pp. 965 - 974
• Main Authors: Porichis, Filippos, Kwon, Douglas S., Zupkosky, Jennifer, Tighe, Daniel P., McMullen, Ashley, Brockman, Mark A., Pavlik, David F., Rodriguez-Garcia, Marta, Pereyra, Florencia, Freeman, Gordon J., Kavanagh, Daniel G., Kaufmann, Daniel E.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 28.07.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Antigens, CD - metabolism; Apoptosis Regulatory Proteins - antagonists & inhibitors; B7-H1 Antigen; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Separation; Cytokines - biosynthesis; Cytokines - immunology; Flow Cytometry; Hematologic and hematopoietic diseases; HIV Infections - immunology; HIV Infections - metabolism; Human viral diseases; Humans; Immunobiology; Immunophenotyping; Infectious diseases; Medical sciences; Programmed Cell Death 1 Receptor; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Infection; Virus; Immunopathology; CD4 T lymphocyte; Hematology; Viral disease; Retroviridae; AIDS; Programmed cell death protein 1; Human immunodeficiency virus; Immune deficiency; Lentivirus
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-12-328070

Defining the T helper functions impaired by programmed death–1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-γ), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T-cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets.