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Table 2 Two-way stimulatory immune checkpoint induces tissue and systemic inflammation (human study)

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

Checkpoint (receptor:ligand)

Disease

Functional change

PMID#

Year

Forward immune checkpoint (towards TC)

 CD40:CD40L

ACS

Lesion CD40L+ TC↑

12732389

2003

Bladder tumor

Peripheral T cell↓ to agonistic IgG1 chimeric α-CD40 Ab

25589626

2015

 CD137:CD137L

AS

CD137↑ in lesion CD8+ TC

18285570

2008

Head/neck cancer

CD4+/CD8+ TC proliferation maker Ki67↑ to CD137 agonist

27496866

2016

 CD134:CD134L

ACS

CD134+ CD4+CD28null TC express INF-γ/TNF-α,

22282196

2012

Colorectal cancer

CD134+ CD8+ TC infiltration enhances prognostic

26439988

2015

 CD27:CD70

NSCLC

Higher CD4/CD8 TC ratio in CD70+ tumor cell

25951351

2015

 CD30:CD30L

Lymphoma

CD30+ Th2 proliferation↓ by CD30L

12855655

2003

 GITR:GITRL

Liver tumor

Tumor-infiltrating Treg-suppressive capacity↓ by GITRL

26587321

2015

Reverse-immune checkpoint (towards APC)

 CD40:CD40L

CVD + CKD

CD40+ MC↑, MC inflammatory markers↑

27992630

2016

Cancer

CD40L mediate TIS-TC induced inflammatory MC/MØ

25375372

2014

 CD137:CD137L

AAS

CD137L+ CD14+ MC↑

24899613

2014

MM

CD137 inhibit MM cell proliferation and induce death

20520765

2010

 CD134:CD134L

ACS

OX40L+ MC↑

22282196

2012

MLC

OX40L+ MLC-DC express higher CD80+/CD86+/HLA-DR

14984494

2004

 CD27:CD70

Lymphoma

Anti-CD70 mediate MØ phagocytosis

17038522

2007

 CD30:CD30L

Lymphoma

Anti-CD30 mediate MØ phagocytosis

17909075

2007

 GITR:GITRL

AS

Plaque MØ activation↑

17067317

2006

  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. ↑ refers to higher population/expression level/activity. ↓ refers to lower population/expression level/activity
  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; MØ 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