Exploring the immunomodulatory role of virtual memory CD8+ T cells: Role of IFN gamma in tumor growth control

Abstract

Virtual memory CD8+ T cells (TVM) have been described as cells with a memory-like phenotype but without previous antigen (Ag) exposure. TVM cells have the ability to respond better to innate stimuli rather than by TCR engagement, producing large amounts of interferon gamma (IFNγ) after stimulation with interleukin (IL)-12 plus IL-18. As a result of the phenotypic similarity, TVM cells have been erroneously included in the central memory T cell subset for many years. However, they can now be discriminated via the CD49d receptor, which is up-regulated only on conventional memory T cells (TMEM) and effector T cells (TEFF) after specific cognate Ag recognition by a TCR. In this work we show that systemic expression of IL-12 plus IL-18 induced an alteration in the normal TVM vs TMEM/TEFF distribution in secondary lymphoid organs and a preferential enrichment of TVM cells in the melanoma (B16) and the pancreatic ductal adenocarcinoma (KPC) tumor models. Using our KPC bearing OT-I mouse model, we observed a significant increase in CD8+ T cell infiltrating the tumor islets after IL-12+IL-18 stimulation with a lower average speed when compared to those from control mice. This finding indicates a stronger interaction of T cells with tumor cells after cytokine stimulation. These results correlate with a significant reduction in tumor size in both tumor models in IL-12+IL-18-treated OT-I mice compared to control OT-I mice. Interestingly, the absence of IFNγ completely abolished the high antitumor capacity induced by IL-12+IL-18 expression, indicating an important role for these cytokines in early tumor growth control. Thus, our studies provide significant new information that indicates an important role of TVM cells in the immune response against cancer.

The Role of IL-18 in P2RX7-Mediated Antitumor Immunity

“…Moreover, IL-18 production and administration was shown to limit the migration of colon MC38 tumor cells into the liver by increasing the activation of NK cells and their cytotoxicity through FASL [102]. Similar results have been shown in pancreatic, metastatic and non-metastatic melanoma mouse models, where in vivo administration of IL-18 slowed tumor growth by increasing the activation and cytotoxicity of CD4+ and CD8+ T cells and NK cells [101,[103][104][105], as well as their interaction with tumor cells and the robust generation of memory T cells [106]. It has also been recently shown that IL-18 administration after bone marrow transplantation induced the cytotoxicity of T cells in a mouse model of myeloma and enhanced their lethality in a leukemia model [107].…”

Premature skewing of T cell receptor clonality and delayed memory expansion in HIV-exposed infants

“…Altogether, these observations possibly suggest non-antigen driven mechanisms that resulted in the loss of diversification of the iHEU TCR repertoire. Factors such as homeostatic proliferation under chronic maternal immune activation and proinflammatory milieu could give rise to virtual T cells 59 – 61 , altered thymic selection since iHEU have been reported to have reduced thymic size relative to iHUU 43 , 62 , or partially dysfunctional RAG system could contribute to iHEU having skewed TCR clonality. Since it is evident that reduced TCR diversity in iHEU is associated with impaired T cell memory differentiation and possibly increasing vulnerability to infection among iHEU 51 , further investigations are required to decipher the mechanism responsible for the skewed TCR clonality in iHEU.…”