Immunoregulatory Receptor



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The healthy immune system employs a series of checkpoints in order to maintain self-tolerance or prevent collateral tissue damage during an immune response. Activation of CD8+ or CD4+ T lymphocytes by antigen-presenting cells (APCs) requires:

  1. requires engagement of the T cell receptor with MHC class I or II molecules, respectively
  2. co-stimulatory signals generated by CD28 (on T cells) binding to CD80 or CD86 (on APCs)
Additional co-stimulatory receptors, such as ICOS and GITR, further promote T cell activation. T cell receptor engagement is coupled with inhibitory signals that repress T cell activation and response. Such signals are elicited by proteins involved in immune checkpoint control such as PD-1, CTLA-4 and TIM-3

PD-1 and CTLA-4 immune checkpoint proteins are commonly upregulated in tumor infiltrating T cells, bind their corresponding ligands, PD-L1/PD-L2 and CD80/86 respectively, and downregulate the T cell response. Immune checkpoint ligands are often upregulated in cancer cells as a means to evade immune detection (1,2). Activating antitumor immunity through the blockade of immune checkpoint proteins has become a promising therapeutic strategy for the treatment of cancer (3,4). There is also increasing interest in understanding the role of immunometabolism through potential therapeutic targets such as IDO and Arginase-1. IDO is an immunosuppressive enzyme involved in tryptophan degradation, which is upregulated in many tumors. Arginase-1 is a ubiquitous enzyme highly expressed by myeloid derived suppressor cells (MDSCs) that are often recruited to the tumor microenvironment. Arginase-1 on MDSCs catalyzes the conversion of L-arginine to urea, thereby depriving T cells of essential nutrients required for their activation and differentiation (5).

Below is a table of stimulatory and inhibitory receptor-ligand complexes, which mediate activation or dampening of the T-cell response, respectively. Click on linked protein names for additional information and related product lists.

Cellular Response T cell Antigen presenting cell
Co-stimulatory CD28 B7-1 (CD80) or B7-2 (CD86)
CD40L CD40
TLT-2?** B7-H3
OX40 (CD134) OX40L
4-1BB (CD137) 4-1BBL
Co-inhibitory CTLA-4 B7-1 (CD80) or B7-2 (CD86)
PD-1 B7-H1 (PD-L1) or B7-DC (PD-L2)
Unknown B7-H3
Unknown B7-H4
Unknown VISTA
VISTA Unknown
TIM-3 Galectin-9

**Myeloid cell-like transcript 2 (TLT-2) has been shown to express the putative receptor for B7-H3 (6,7). However its co-stimulatory nature and whether it, indeed, interacts with B7-H3 have been challenged (8). Hence the validity of this receptor-ligand interaction is a matter of debate.


  1. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252–64.
  2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8(8), 793–800.
  3. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–65.
  4. Brahmer JR, Pardoll DM (2013) Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 1(2), 85–91.
  5. Draghiciu O, Lubbers J, Nijman HW, Daemen T (2015) Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology 4(1), e954829.
  6. Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc. Natl. Acad. Sci. U.S.A. 105(30), 10495–500.
  7. Kobori H, Hashiguchi M, Piao J, Kato M, Ritprajak P, Azuma M (2010) Enhancement of effector CD8+ T-cell function by tumour-associated B7-H3 and modulation of its counter-receptor triggering receptor expressed on myeloid cell-like transcript 2 at tumour sites. Immunology 130(3), 363–73.
  8. Leitner J, Klauser C, Pickl WF, Stöckl J, Majdic O, Bardet AF, Kreil DP, Dong C, Yamazaki T, Zlabinger G, Pfistershammer K, Steinberger P (2009) B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur. J. Immunol. 39(7), 1754–64.