Increased expression of TIGIT on CD4+ T cells ameliorates immune-mediated bone marrow failure of aplastic anemia.

Abstract

Aplastic anemia (AA) is an autoimmune disease in which T cell activation is suspected to play an important role. T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) is an inhibitory receptor, which exhibits inhibitory functions on the immune response. However, its role in AA has not been clearly determined. In the current study, we showed that the frequency of TIGIT-positive CD4(+) T cells was reduced in the vast majority of AA patients (85%, 17/20). In TIGIT-silenced human CD4(+) T cells, stimulation of agonistic anti-TIGIT monoclonal antibody significantly facilitated cell proliferation, increased production of IL-2 and IFN-γ, and inhibited production of IL-10. However, in TIGIT-overexpressed human CD4(+) T cells, cell proliferation and the production of IL-2, IFN-γ, and TNF-α were significantly hindered; in contrast, the secretion of IL-10 was improved. RT-PCR and Western blotting showed that T-bet expression in human CD4(+) T cells was significantly decreased by TIGIT overexpression, but only slightly altered by TIGIT knockdown. In mouse models, lentivirus-mediated TIGIT-overexpressed CD4(+) T cell transfer significantly rescued the decreased red blood cell count, attenuated the increase in serum INF-γ and TNF-α levels, and lengthened the median survival time. The mRNA levels of CD34, stem cell factor (SCF), and granulocyte/macrophage-colony-stimulating factor (GM-CSF) in bone marrow mononuclear cells were also up-regulated. In conclusion, increased expression of TIGIT could inhibit the function of CD4(+) T cells in vitro and ameliorate immune-mediated bone marrow failure of AA in vivo providing a new potential strategy for the treatment of AA.