CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection.
Expansion of PD-1-expressing CD8+cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion. Here, we developed AdVova-infected B6 and transgenic CD11c-DTR (termed AdVova-B6 and AdVova-CD11c-DTR) mice with chronic infection, and assessed a potential effect of CD40 agonist on the conversion of CTL exhaustion and on a potential enhancement of PD-1 antagonist action in rescuing exhausted CTLs in our chronic infection models. We demonstrate that a single dose of anti-CD40 alone can effectively convert CTL exhaustion by activating the mTORC1 pathway, leading to CTL proliferation, up-regulation of an effector-cytokine IFN-γ and the cytolytic effect in AdVova-B6 mice. Using anti-CD4 antibody and diphtheria toxin (DT) to deplete CD4+T-cells and dendritic cells (DCs), we discovered that the CD40 agonist-induced conversion in AdVova-B6 and AdVova-CD11c-DTR mice is dependent upon host CD4+T-cell and DC involvements. Moreover, CD40 agonist significantly enhances PD-1 antagonist effectiveness in rescuing exhausted CTLs in chronic infection. Taken together, our data demonstrate the importance of CD40 signaling in the conversion of CTL exhaustion and its ability to enhance PD-1 antagonist action in rescuing exhausted CTLs in chronic infection. Therefore, our findings may positively impact the design of new therapeutic strategies for chronic infectious diseases.
Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada; Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Aizhang
A
Xu
Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada; Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Rong
R
Wang
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Andrew
A
Freywald
Department of Internal Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Kristoffor
K
Stewart
School of Public Health, University of Saskatchewan, Canada.
Suresh
S
Tikoo
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Jianqing
J
Xu
Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Changyu
C
Zheng
Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada; Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Electronic address: jim.xiang@usask.ca.
Jim
J
Xiang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D007239:Infections / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D046912:Multiprotein Complexes; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
CD40 agonist; CTL exhaustion; Chronic infection; PD-1 antagonist; mTORC1 pathway