IL-2-Activated CD8+CD44high Cells Express Both Adaptive and Innate Immune System Receptors and Demonstrate Specificity for Syngeneic Tumor Cells

Abstract

CD8+ T cells depend on the αβ TCR for Ag recognition and function. However, Ag-activated CD8+ T cells can also express receptors of the innate immune system. In this study, we examined the expression of NK receptors on a population of CD8+ T cells expressing high levels of CD44 (CD8+CD44high cells) from normal mice. These cells are distinct from conventional memory CD8+ T cells and they proliferate and become activated in response to IL 2 via a CD48/CD2-dependent mechanism. Before activation, they express low or undetectable levels of NK receptors but upon activation with IL-2 they expressed significant levels of activating NK receptors including 2B4 and NKG2D. Interestingly, the IL-2-activated cells demonstrate a preference in the killing of syngeneic tumor cells. This killing of syngeneic tumor cells was greatly enhanced by the expression of the NKG2D ligand Rae-1 on the target cell. In contrast to conventional CD8+ T cells, IL-2-activated CD8+CD44high cells express DAP12, an adaptor molecule that is normally expressed in activated NK cells. These observations indicate that activated CD8+CD44high cells express receptors of both the adaptive and innate immune system and may play a unique role in the surveillance of host cells that have been altered by infection or transformation.

Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

“…15 The CTL activity of activated CD8 T cells against RMA, RMA-Rae-1␦ target cells was assessed at a ratio of 10 effector T cells to 1 target cell in a 4-hour 51 Cr-release assay. For redirected lysis experiments, day-4 activated CD8 T cells were preincubated with the indicated mAb (10 g/mL) for 15 minutes.…”

“…13,14 We have recently showed that CD8 ϩ CD44 hi T cells from normal mice possess characteristics of both T cells and NK cells. 15 These cells are activated in response to IL-2 alone and show self-reactivity in that they preferentially kill syngeneic tumor cells. Furthermore, CD8 ϩ CD44 hi T cells express NK receptors upon activation, and engagement of these NK receptors enhances the ability of the cells to lyse syngeneic tumor cells.…”

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

“…8 In prostate cancer patients, tumorderived exosomes downregulated NKG2D expression on circulating CD8 C T cells. 9 Recent NKG2D regulation studies showed that many cytokines influence NKG2D expression on CD8 C T and NK cells, including the NKG2D-promoting cytokines interleukin (IL)-2, IL-7, and IL-12 [10][11][12] ; the NKG2D-suppressing cytokines IL-4 and transforming growth factor-b; and interferon-g, at high levels. 13,14 However, the mechanisms of NKG2D regulation on CD8 C T cells remain poorly investigated.…”

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

“…In addition to the antigen-specific immune response, the host has an increase in cytokines, NK cells, macrophages and memory T cell activation. 65,66 These recruited immune effector cells can cause MHC independent killing of tumor cells and cytokines that result in a bystander T cell response 67 that can also control tumor growth 68 (Figure 1b). Moreover, the innate immune system can detect CMV DNA via toll-like receptor (TLR) 9 and cyclic GMP/AMP synthase (cGAS) catalyzing formation of stimulator of interferon genes (STING) followed by an upregulation of type I interferon responses 69,70 that may cause indirect killing of tumor cells.…”