*Purpose: The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CD226, two poliovirus receptor-like proteins, are an emerging group of immune checkpoints with immunomodulatory functions in both T and NK cells. The immunomodulation is mediated through their interaction with the plausible dominant ligand CD155, and CD112. Interaction of CD226 with the ligands costimulates T cell, whereas TIGIT exerts the opposite effect and inhibits T cell response. This ligand/receptor network is a novel co-stimulatory pathway that regulates human T cell responses and has been shown to play an important role in various autoimmune diseases and cancer. In murine models of transplantation inhibition of TIGIT/CD226 pathway is shown to be critical for promoting tolerance by increasing the Tregs and suppressing T effector response. We have previously observed increased expression levels of CD226 and its ligands CD155 and CD112 in both peripheral T and NK cell populations in kidney transplant recipients (KTR) versus healthy controls (HC).

*Methods: To further understand the relevance of TIGIT/CD226 cosignaling in transplantation we examined the expression levels of all the four above mentioned receptor-ligand molecules following stimulation through TCR activation and the impact of blocking CD226 and/or CD112 on cytokine production post stimulation.

*Results: Our results show that T cells in both KTR and HC groups significantly upregulated TIGIT and CD226 post stimulation and the expression levels of both TIGIT and CD226 post stimulation between the HC and KTR were not significantly different. Both the ligands also showed a similar pattern of upregulation and levels of expression in T cells. In contrast the NK cells from KTR showed a different pattern of upregulation. TIGIT and CD155 were upregulated to similar levels in NK cells in both KTR and HC post stimulation. However, both CD226 and CD112 expression were significantly upregulated in NK cells in the KTR group unlike the HC group where there was no significant change. This demonstrates an inflammatory response in KTR that results for an interaction between CD226 and CD112 in the NK cells. However, blocking blocking CD226 and/or CD112 during stimulation had no significant change on cytokine production (IFN-γ, IL-12 and IL-10) post stimulation.

*Conclusions:  An inflammatory response in KTR possibly results from an interaction between CD226 and CD112 in the NK cells.

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