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Table 3 Two-way stimulatory immune checkpoint induces tissue and systemic inflammation (mouse study)

From: Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation

Checkpoint (receptor:ligand) Genotype Disease Functional change PMID# Year
Forward immune checkpoint (towards TC)
 CD40:CD40L CD40−/−APOE−/− AS Spleen memory CD4+/CD8+ TC↓ 20100871 2007
Rag1−/− Lung CA Tumor Th1/Th17↑, Treg/Th2↓ to CD40 agonist 25651850 2015
 CD137:CD137L APOE−/− AS Lesion CD3+/CD8+ TC↑ to CD137 agonist 18285570 2008
NSG Osteosarcoma Ameliorate CAR TC exhaustion to CD137 25939063 2015
 CD134:CD134L LDLR−/− AS Lesion CD3+ TC↓ to α-OX40L 24068673 2013
C57BL/6 Mammary CA Blood effector/memory TC↑ to α-OX40+Dribbles 27874054 2016
 CD27:CD70 CD70−/−LDLR−/− AS Spleen Treg↓ 27786334 2017
CD27−/− Solid tumor Spleen Treg↓, tumor CD3+ TC infiltration↑ 22628427 2012
 CD30:CD30L LDLR−/− AS Adventitial CD3+ TC↓ to α-CD30L 23087358 2012
C57BL/6 Fibrosarcoma CD30+ Vδ TC drives cancer progression 27384869 2016
 GITR:GITRL LDLR−/−GITRLTG AS Lymph node Terg/effector memory CD4+ TC↑ 27444204 2016
Reverse-immune checkpoint (towards APC)
 CD40:CD40L CD40−/−APOE−/− AS Blood Ly6C+ MC↓, aorta M1 MØ↓ 20100871 2007
KPC Pancreatic CA Tumor M1 MØ↑ to CD40 agonist 21436454 2011
 CD137:CD137L CD137−/−APOE−/− AS Aorta CD11b+ MC/MØ↓ 25059229 2014
C57BL/6 Liver CA Tumor iNOS-positive MØ↑ to CD137 agonist 24789574 2014
 CD134:CD134L OX40L−/−APOE−/− AS VEGF-induced angiogenesis↓ 20584752 2010
C57BL/6 Sarcoma Tumor M1 MØ↑ to CD134 agonist 22578109 2012
 CD27:CD70 CD70TG APOE−/− AS Circulating MC viability↓ 20505312 2010
SCID Lymphoma Delete MØ reduce survival to α-CD70 17038522 2007
 CD30:CD30L LDLR−/− AS Lesion MØ/BC no affect 23087358 2012
SCID Lymphoma Delete MØ reduce survival to α-CD30 17909075 2007
GITR:GITRL C57BL/6 Liver tumor Tumor M1 MØ↑ to GITR agonist+sunitinib 26239999 2016
  1. Stimulatory immune checkpoint has been described in human and mouse metabolic diseases. For example, CD40:CD40L two-way stimulatory immune checkpoint was activated and associated with increased lesion CD40L+ TC in ACS and CD40+ MC in CKD in humans. CD40 KO reduced spleen effector memory CD4+/CD8+ TC and blood Ly6C+ MC and aorta M1 MΦ. Similar functional change was observed for immune checkpoint CD40:CD40L CD137:CD137L and OX40:OX40L
  2. Abbreviation: AAS acute atherothrombotic stroke; CAR chimeric antigen receptor; CKD chronic kidney disease; CVD cardiovascular disease; CA carcinoma; EC endothelial cell; GITR glucocorticoid-induced TNFR-related protein; GITRL GITR ligand; KPC KrasLSL-G12D/+, Trp53LSL-R172H/+, Pdx1-Cre; MC monocyte; macrophage; mAb agonist monoclonal antibodies; MM multiple myeloma; MLC myeloid leukemia cell; NSCLC non-small cell lung cancer; NKC natural killer cell; SCID severe combined immunodeficient; TC T cell; Treg regulatory T cell; TG transgene; TIS tumor induce Senescent; VEGF vascular endothelial growth factor