GITR/GITRL: More than an effector T cell co‐stimulatory system

Nocentini, Giuseppe; Ronchetti, Simona; Cuzzocrea, Salvatore; Riccardi, Carlo

doi:10.1002/eji.200636933

Cited by 120 publications

(128 citation statements)

References 36 publications

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“…In recent years, their role in immunity has been expanded to DC and natural killer (NK) cells (13). Our studies identified a functional form of TNF family members that can activate its cognate receptor.…”

Section: Discussionmentioning

confidence: 95%

Structural basis for ligand-mediated mouse GITR activation

Zhou¹,

Tone²,

Song³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoid-induced TNF receptor ligand (GITRL) is a member of the TNF super family (TNFSF). GITRL plays an important role in controlling regulatory T cells. The crystal structure of the mouse GITRL (mGITRL) was determined to 1.8-Å resolution. Contrary to the current paradigm that all ligands in the TNFSF are trimeric, mGITRL associates as dimer through a unique C terminus tethering arm. Analytical ultracentrifuge studies revealed that in solution, the recombinant mGITRL exists as monomers at low concentrations and as dimers at high concentrations. Biochemical studies confirmed that the mGITRL dimer is biologically active. Removal of the three terminal residues in the C terminus resulted in enhanced receptor-mediated NF-B activation than by the wild-type receptor complex. However, deletion of the tethering C-terminus arm led to reduced activity. Our studies suggest that the mGITRL may undergo a dynamic population shift among different oligomeric forms via C terminus-mediated conformational changes. We hypothesize that specific oligomeric forms of GITRL may be used as a means to differentially control GITR receptor signaling in diverse cells.costimulation ͉ oligomerization ͉ regulatory ͉ T cell ͉ TNF

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Section: Discussionmentioning

confidence: 95%

Structural basis for ligand-mediated mouse GITR activation

Zhou¹,

Tone²,

Song³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Important examples of the latter are CD27L, 41BBL, and glucocorticoidinduced TNF receptor ligand (GITRL) 4 , controlling various facets of the T cell response, and CD40L, providing a pivotal costimulatory signal to APCs, such as dendritic cells (DCs) and B cells (1)(2)(3)(4)(5). In accordance with these regulatory functions, the aforementioned ligands have been implicated in the development of autoimmune disease, but they also represent attractive targets for cancer immunotherapy.…”

mentioning

confidence: 99%

Trimer Stabilization, Oligomerization, and Antibody-Mediated Cell Surface Immobilization Improve the Activity of Soluble Trimers of CD27L, CD40L, 41BBL, and Glucocorticoid-Induced TNF Receptor Ligand

Wyzgol

Müller

Fick

et al. 2009

The Journal of Immunology

124

131

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For many ligands of the TNF family, trimer stability and oligomerization status are crucial determinants of receptor activation. However, for the immunostimulatory ligands CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand (GITRL) detailed information regarding these requirements is lacking. Here, we comprehensively evaluated the effect of trimer stability and oligomerization on receptor activation by these ligands. Treatment with soluble Flag-tagged CD27L, 41BBL, and GITRL minimally activated receptor signaling, while Flag-CD40L was highly active. Oligomerization with anti-Flag Abs further enhanced the specific activity of Flag-CD40L 10-fold and of Flag-41BBL more than 200-fold, but it failed to activate Flag-CD27L and Flag-GITRL. We next investigated the relevance of trimer stability by introducing the tenascin-C (TNC) trimerization domain, yielding stabilized Flag-TNC-ligand trimers. Oligomerization with anti-Flag Ab potently activated signaling by Flag-TNC-CD27L and Flag-TNC-GITRL and, albeit to a lesser extent, Flag-TNC-CD40L and Flag-TNC-41BBL. Forced hexamerization, by introducing an Ig Fc domain, revealed that hexameric derivatives of Flag-TNC-41BBL, Flag-CD40L, and Flag-TNC-GITRL all activate receptor signaling with high efficiency, whereas hexameric Flag-CD27L variant left inactive. Finally, we attempted to selectively activate receptor signaling on targeted cells, by using Ab fragment (single-chain fragment variable region, scFv)-ligand fusion proteins, an approach previously applied to other TNF ligands. Target cell surface Ag-selective activation was achieved for scFv-41BBL, scFv-CD40L, and scFv-GITRL, although the latter two displayed already significant activity toward Ag-negative cells. In conclusion, our data establish that trimeric CD40L is active, 41BBL requires hexamerization, GITRL requires trimer stabilization, and CD27L requires trimer stabilization and oligomerization. Furthermore, surface immobilization might be exploited to gain locally enhanced ligand activity.

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“…Glucocorticoid-induced TNFR (GITR) and its ligand, GITRL, are recently described members of the TNFR/ligand superfamilies and are implicated in a wide range of immune functions involving both effector and regulatory T cells (Tregs) (3)(4)(5). GITR is expressed at low levels on resting mouse and human T cells and is up-regulated upon activation of CD4 ϩ and CD8 ϩ T cells.…”

mentioning

confidence: 99%

Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

Chattopadhyay

Ramagopal²,

Brenowitz³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique ''domain-swapping'' interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structureguided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.crystal structure ͉ domain swap ͉ oligomerization ͉ T cell costimulation

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GITR/GITRL: More than an effector T cell co‐stimulatory system

Cited by 120 publications

References 36 publications

Structural basis for ligand-mediated mouse GITR activation

Structural basis for ligand-mediated mouse GITR activation

Trimer Stabilization, Oligomerization, and Antibody-Mediated Cell Surface Immobilization Improve the Activity of Soluble Trimers of CD27L, CD40L, 41BBL, and Glucocorticoid-Induced TNF Receptor Ligand

Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

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