1q25.1

AITRL,GITRL,TL6,TNLG2A,hGITRL

Host-tumor interaction

In mice, it has been shown that application of the agonistic GITR antibody DTA-1 delays tumor progression and can even lead to complete tumor rejection. Similar results were obtained by using GITRL-Fc fusion protein. Transfection of tumor cells with GITRL causes rejection of the tumor and prolonged survival, while parental cells cannot be rejected. This effect can be reversed by administration of a blocking GITRL antibody. There is evidence that expression of GITRL promotes the development of tumor-specific T cells. Re-challenge of mice which once successfully rejected GITRL-positive tumor results in complete rejection of both transfected and non-transfected tumors. Several studies showed increased infiltration of CD8+ cells in GITRL-expressing tumors. By the use of depletion experiments and athymic nude mice it has been shown that for GITR-GITRL dependent rejection of tumors both CD4+ and CD8+ T cells as well as NK cells are required.
In humans, controversial data regarding the function of GITR and GITRL in tumor immunology were described. Hanabuchi et al. reported that NK cells are activated by engagement of GITRL on plasmacytoid dendritic cells, which can be blocked by anti-GITRL antibody. In contrast, Baltz et al. and Baessler et al. demonstrated substantial GITRL expression on tumor cells and leukemic blasts resulting in diminished NK cell reactivity. Blockade of GITR-GITRL interaction by anti-GITR antibody abrogated the inhibitory effect of GITRL. Furthermore, stimulation of GITRL substantially induced the production of TGF-beta and IL-10 by tumor cells and leukemic blasts. Additionally, they reported that human GITRL is released by tumor cells in a soluble form which impairs NK cell reactivity alike the membrane-bound form. Thus, GITRL expression seems to affect the interaction of human tumor cells with the immune system by influencing tumor cell immunogenity and metastasis and creating an immunosuppressive cytokine microenvironment. The inhibitory effect of GITRL on human NK cells was further supported by Liu et al., who reported inhibition of NK cell proliferation and cytokine production and increased apoptosis after GITR stimulation. These controversial data regarding the function of GITR on human NK cells may be due to the usage of different reagents and different experimental condition.
The results regarding the role of GITR and GITRL in tumor immunology are controversial in mice and humans. Thus, GITR and GITRL may mediate different effects in mice and men, and in line suppression of human regulatory T cells, in contrast to their murine counterparts, is not inhibited by GITR. Many studies employed agonistic antibodies or recombinant protein for GITR stimulation and not constitutively GITRL-expressing cells. Thus, these studies do not involve possible influences of reverse signaling mediated by GITRL, which may change reaction of GITRL-bearing cells and may in turn alter functions of GITR-bearing cells.

Autoimmune disease

The influence of GITR and GITRL was tested in different mouse models of autoimmune disease. Onset of autoimmune diabetes in NOD mice is accelerated if they are treated with agonistic GITR mAb, and activation of CD4+ T cells is increased compared to control treated mice. Likewise, application of a blocking GITRL antibody protected from diabetes. In GITR -/- mice, experimental autoimmune diseases take an attenuated course. GITR -/- mice with collagen-induced arthritis show less joint inflammation and bone erosion than wildtype mice. Furthermore, lower concentrations of inflammatory mediators were reported. In line with these findings, GITR triggering antibody exacerbates collagen-induced arthritis in wildtype mice compared to control-treated siblings.
However, all these studies regarding the function of GITR and its ligand in autoimmune disease were performed in mice. Further investigation is needed to elucidate the relevance of GITR and GITR ligand in human autoimmune disease and to clarify the similarities and differences of these molecules in mice and men.