GITR: A Modulator of Regulatory and Effector T‐Cell Activity, Crucial in Tumour Rejection and Autoimmune Diseases

Abstract

The immune response is the result of complex interactions among cells of innate immunity, the vascular system and cells of adaptive immunity including T and B lymphocytes. Interactions among effector T cells, regulatory T cells (Tregs) and antigen‐presenting cells determine the outcome of the immune response. Activated effector T cells and Tregs express high levels of glucocorticoid‐induced tumour necrosis factor receptor‐related protein (GITR, also known as TNFRSF18 or CD357), which is triggered by the ligands GITRL and SECTM1. The effect of GITR triggering on the immune system is complex, with GITR playing a physiological role in inflammation, response to infection, graft rejection, autoimmunity and tumours. Antibodies and fusion proteins capable of modulating GITR and GITRL activity produce meaningful effects in animal models of advanced tumours and boost the effectiveness of vaccines. GITR triggering also shows potential for curing autoimmune diseases and preventing graft rejection and graft‐versus‐host disease.

Key Concepts

  • GITR is a costimulatory molecule that is overexpressed by activated T lymphocytes and promotes their activation/expansion following activation by its ligand (GITRL).
  • GITR triggering can treat infection, particularly chronic viral infection, and boost the effectiveness of vaccines.
  • Inhibition of GITR triggering by fusion proteins has an anti‐inflammatory effect.
  • The highest levels of GITR expression are found in regulatory T cells (Tregs).
  • GITR plays a crucial role in the development of FoxP3+ Tregs in the thymus (tTregs) and the expansion of tTregs and peripherally derived Tregs (pTregs).
  • A subset of CD4+ pTregs that expresses GITR, but not FoxP3 or CD25, is expanded in patients with autoimmune diseases who show low disease activity.
  • In mouse models, GITR triggering by anti‐GITR antibodies promotes the rejection of established tumours via effector T lymphocyte activation and, more importantly, via Treg killing by antibody‐dependent cell‐mediated cytotoxicity, Treg inhibition/differentiation and modulation of Treg trafficking.
  • The GITR/GITRL system is structurally different in mice and humans, suggesting that functional differences also exist.
  • Phase I studies testing anti‐human GITR antibodies in cancer patients are underway.

Keywords: tumour necrosis factor receptor superfamily; T lymphocyte costimulation; antibody‐dependent cell‐mediated cytotoxicity (ADCC); antitumour treatment; vaccines; antiinfective treatment; antiinflammatory treatment; Treg markers; Treg expansion; autoimmune disease pathogenesis

Figure 1. GITR expression in murine CD4+ T lymphocytes. (a) Flow cytometry experiments show that more than 90% of CD4+ T lymphocytes from healthy wild‐type mice express GITR. GITR expression by CD4+ T lymphocytes from GITR KO mice is shown as a negative control. Murine CD8+ T lymphocytes from wild‐type mice express GITR in a similar way (not shown). (b) About 30% of CD4+ T lymphocytes from healthy wild‐type mice express GITR at intermediate levels (GITRint) or high levels (GITRbright).
Figure 2. Structures of murine and human GITR and GITRL. Murine GITRL exists as a dimer and has a high binding affinity for murine GITR, generating a strong signal. In contrast, human GITRL can exist as a monomer, dimer, trimer or supercluster. GITR binding by a GITRL monomer or dimer generates a very weak signal, whereas GITR binding by a GITRL supercluster generates a strong signal.
Figure 3. GITR triggering in effector T cells. GITRL triggering in murine CD4+ and CD8+ effector cells has effects similar to those seen using anti‐GITR Ab (e.g. DTA‐1 Ab). The specific effects depend on cell activation status and level of GITR activation.
Figure 4. GITR triggering in Tregs. The effects of triggering by GITRL differ from those triggered by anti‐GITR Ab (e.g. DTA‐1 Ab). The effects triggered by GITRL shown here represent the long‐term effects of physiological or supraphysiological GITRL levels in murine Tregs. The effects triggered by anti‐GITR Ab shown here represent acute effects of pharmacological doses in tumour‐infiltrating Tregs (except for inhibition of suppressive activity, which is observed following in vitro triggering).
Figure 5. GITR‐activated pathways in murine T lymphocytes. Green arrows indicate activation (e.g. GITR‐dependent TRAF5 activation) or increased expression (e.g. STAT6‐dependent upregulation of IL‐9 transcription). Red arrows indicate inhibition (e.g. TRAF5‐dependent TRAF3 inhibition) or decreased expression (e.g. HDAC‐dependent inhibition of FoxP3 transcription). These effects are dependent on the specific cell subset, cell activation status and possibly the level of GITR activation (ligand affinity). Some of these pathways differ in human T cells (e.g. hGITR activates TRAF2 signalling).
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Further Reading

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Nocentini G and Riccardi C (2009) GITR: a modulator of immune response and inflammation. Advances in Experimental Medicine and Biology 647: 156–173.

Nocentini G, Ronchetti S, Petrillo MG, et al. (2012) Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. British Journal of Pharmacology 165 (7): 2089–2099.

Petrillo MG, Ronchetti S, Ricci E, et al. (2015) GITR+ regulatory T cells in the treatment of autoimmune diseases. Autoimmunity Reviews 14 (2): 117–126.

Ronchetti S, Ricci E, Petrillo MG, et al. (2015) Glucocorticoid‐induced tumour necrosis factor receptor‐related protein: a key marker of functional regulatory T cells. Journal of Immunology Research 2015: 171520.

Sanmamed MF, Pastor F, Rodriguez A, et al. (2015) Agonists of co‐stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Seminars in Oncology 42 (4): 640–655.

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Snell LM, Lin GH, McPherson AJ, et al. (2011) T‐cell intrinsic effects of GITR and 4‐1BB during viral infection and cancer immunotherapy. Immunological Reviews 244 (1): 197–217.

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Nocentini, Giuseppe, Cari, Luigi, and Riccardi, Carlo(Jan 2017) GITR: A Modulator of Regulatory and Effector T‐Cell Activity, Crucial in Tumour Rejection and Autoimmune Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026242]