HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT)

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT’s ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.

HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors

“…It has been reported that HTLV-1 infected cells and ATL cells express both co-stimulatory (OX40) and co-inhibitory receptors (PD-1 and TIGIT) on their surfaces [23, 25, 34, 35]. These findings suggest that HTLV-1 influences expression of co-inhibitory and co-stimulatory receptors.…”

“…Increased TIGIT expression competes with CD226, a co-stimulatory receptor, for binding with CD155, resulting in inhibition of T-cell activation [47]. In addition, HBZ suppressed CD226 expression [25]. Furthermore, our previous study indicated that TIGIT expressed on T cells is implicated in immune suppression through enhanced production of IL-10 from T cells and DC by reverse signaling [25].…”

“…In addition, HBZ suppressed CD226 expression [25]. Furthermore, our previous study indicated that TIGIT expressed on T cells is implicated in immune suppression through enhanced production of IL-10 from T cells and DC by reverse signaling [25]. Since reverse signal from PD-L1 and L2 on DC is also associated with suppressive phenotype of DC and moderate increase in IL-10 expression [48], PD-1 on T cells is also implicated in immune suppression.…”

“…DC-T-cell interaction plays a key role in immune responses to viral infections [49]. We have reported that increased expression of TIGIT on HBZ expressing T cells induces IL-10 production [25]. Furthermore, IL-12p40 production of DC cells was severely impaired in HBZ-Tg mice, which is likely caused by TIGIT on T cells [25, 47].…”

“…It has been reported that ATL cells and HTLV-1 infected cells express the co-inhibitory receptors PD-1 and T cell immunoglobulin and ITIM domain (TIGIT) on their surfaces [23–25]. Binding of one of these receptors to its ligand sends a suppressive signal through the ITIM or ITSM motif in the cytoplasmic region of the receptor [21].…”