ABSTRACT/PROJECT SUMMARY
Acute kidney injury (AKI) occurs at a high rate in both native kidneys and allografts and has no specific therapy
available. Prior studies have established T cell activation and trafficking as an important mechanism that
modulate ischemia reperfusion (IR) and nephrotoxic AKI, along with other overlapping immune and non-
immune mechanisms. Furthermore, AKI is common in patients treated with immune checkpoint inhibitors
targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death receptor 1 (PD1) for
multiple cancers. Our preliminary data using RNA sequencing and flow cytometry shows significant expression
of novel immune checkpoint molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT) in T cells from
post IR mouse kidney and ischemic human kidney. Recently published data suggest that TIGIT co-inhibitory
activity modifies Th1 and Th17 responses, plus regulates Treg suppression activity. Our preliminary data shows
that TIGIT expressing T cells in mouse kidney are highly activated and produce proinflammatory cytokines after
IR. Importantly, mice lacking TIGIT (TIGIT KO) were protected from AKI in IR and Cisplatin AKI models,
suggesting detrimental role for TIGIT during AKI. Therefore, understanding TIGIT-mediated inflammatory
response during AKI is critical for developing novel AKI therapy and to mitigate kidney adverse effects of
immune checkpoint therapies. The central hypothesis of this proposal is that TIGIT promotes proinflammatory
functions of kidney T cells and impairs Treg suppression function. To test this hypothesis, we will (Aim 1)
investigate phenotypic, functional and transcriptional effects of TIGIT in mouse kidney T cells using in vitro and
in vivo approaches. We will further investigate the functional relationship between TIGIT and its co-signaling
partners (CD226, CD155) and other co-inhibitory molecules (PD1, CTLA4) in regulating kidney T cell functions
at baseline and during AKI. Additionally (Aim 2), we will test the hypothesis that T cell specific TIGIT activity is
the major mechanism that drives AKI and impairs repair process using adoptive transfer approaches, in vivo
anti-TIGIT agonist/antagonist antibody effects on AKI outcome in WT and TIGIT KO mice and blocking TIGIT
signaling in repair phase after established AKI. Finally (Aim 3), we will investigate functional effects of TIGIT
expression in human kidney T cells in patients with renal cell carcinoma and live donor biopsies. We will also
evaluate TIGIT expression on T cells isolated from ischemic deceased donor kidney samples and
transcriptional effects at single cell level in T cells from live donor kidney. Results from these studies will be the
first to provide important information on TIGIT mediated effect in kidney T cell functions, therapeutic potential of
targeting TIGIT for AKI treatment and set the stage for future pre-clinical and clinical studies.