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

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor. HBZ promotes this proliferation by influencing the expression and function of multiple co-inhibitory receptors. HBZ suppresses the expression of BTLA and LAIR-1 in HBZ expressing T cells and ATL cells. Expression of T cell immunoglobulin and ITIM domain (TIGIT) and Programmed cell death 1 (PD-1) was enhanced, but their suppressive effect on T-cell proliferation was functionally impaired. HBZ inhibits the co-localization of SHP-2 and PD-1 in T cells, thereby leading to impaired inhibition of T-cell proliferation and suppressed dephosphorylation of ZAP-70 and CD3ζ. HBZ does this by interacting with THEMIS, which associates with Grb2 and SHP-2. Thus, HBZ interacts with the SHP containing complex, impedes the suppressive signal from PD-1 and TIGIT, and enhances the proliferation of T cells. Although HBZ was present in both the nucleus and the cytoplasm of T cells, HBZ was localized largely in the nucleus by suppressed expression of THEMIS by shRNA. This indicates that THEMIS is responsible for cytoplasmic localization of HBZ in T cells. Since THEMIS is expressed only in T-lineage cells, HBZ mediated inhibition of the suppressive effects of co-inhibitory receptors accounts for how HTLV-1 induces proliferation only of T cells in vivo. This study reveals that HBZ targets co-inhibitory receptors to cause the proliferation of infected cells.

Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells

“…2 B ). This finding is compatible with the previous studies that showed that HBZ promotes T-cell growth by enhancing signals through CD3 and that KD of HBZ suppresses the proliferation of ATL cells, including MT-1 cells ( 12 , 48 , 49 ). The alternation of expression of Tax and HBZ seems to execute cooperative programs for survival and proliferation rather than cause them to interfere with each other.…”

Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development

“…These observations suggest that coinfection with S. stercoralis or IDH promotes both de novo infection and cell proliferation, which depend on Tax and HBZ, respectively. This idea is compatible with the fact that T‐cell activation enhances the activities of Tax and HBZ on cell proliferation in primary T cells . Thus, inflammation and T‐cell activation caused by the coinfective agent may increase the risk of ATL development in HTLV‐1 positive individuals.…”

“…Anti‐HBZ CTL are less frequent than anti‐Tax CTL in HTLV‐1‐infected subjects despite the constant expression of HBZ, implying that the immunogenicity of HBZ is low . In addition, HBZ suppresses the intracellular inhibitory signal through TIGIT by inactivation of SHP‐2 and, consequently, enhances cell proliferation upon TCR stimulation . Taken together, these reports indicate that Tax stimulates many oncogenic pathways while HBZ counterbalances the negative effects of Tax, leading to malignant transformation of infected cells.…”

“…This idea is compatible with the fact that T-cell activation enhances the activities of Tax and HBZ on cell proliferation in primary T cells. 19,41,62 Thus, inflammation…”

Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies

“…However, results from another study show that high PD-L1 expression in advanced stages of EBV + ENKTL correlates with improves OS,88 further studies being warranted to establish the prognostic value of PD-L1 expression in these cases. In adult T-cell leukemia/lymphoma (ATLL), HTLV-1 bZIP factor expressed by HTLV-1 infected cells upregulates PD-1 expression on both neoplastic and normal CD4 + T cells, but impedes its suppressive signals by inhibiting co-localization of PD-1 and tyrosine phosphatase (SHP-2), favoring the proliferation of infected cells and immune suppression 89,90. Both asymptomatic HTLV-1 carriers and ATLL patients express high PD-1 levels on HTLV-1-specific cytotoxic T cells, with elevated levels in patients with EBV and CMV co-infection.…”