Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Abstract

During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short-and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than shortlived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.apoptosis | cytokine signaling | interleukin 15 | interleukin 7 | lymphocytic choriomeningitis virus M emory CD8 T cells form from a much larger effector population and provide long-term immunity against subsequent infections via rapid reactivation. The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival. IL-2, IL-7, and IL-15 promote the expansion and survival of activated T cells (2). As memory CD8 T cells form following acute viral infection, two of these cytokines, IL-15 and IL-7, direct memory T cell survival and homeostasis (3, 4). Downstream of their specific receptors, IL-7 and IL-15 activate two primary pathways: janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphoinositide 3-kinase (PI3K)/AK-transforming (AKT). Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).Early models predicted that effector CD8 T-cell contraction was a result of deprivation of T-cell growth factor cytokines that wane during the later stages of infection and that survival was determined via the stochastic interaction of effector T cells with these cytokines. However, effector CD8 T cells are a heterogeneous population composed of cells with varying intrinsic potential for survival and differentiation into memory cells (3,7,8). During several types of infections [such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), Listeria monocytogenes, and Toxoplasma gondii], most of the effector CD8 T cells terminally differentiate and become short-lived, but ...

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

“…Thus, NKG2D enhances PI3K signaling during memory commitment. Interestingly, increased PI3K signaling impairs CD122 expression (25), which corresponds with our observation that Klrk1 2/2 cells have higher CD122 expression during memory commitment (Supplemental Fig. 2D).…”

“…Our findings are remarkable, because PI3K is thought to enhance effector and impair memory cell differentiation (25). In our experiments, IL-15-induced PI3K signaling plays a vital role early during memory commitment.…”

“…This allows T-bet expression and impairs Eomes-mediated memory differentiation (31). Indeed, overexpression of PI3K impairs CD8 memory formation and enhances effector responses (25). It is therefore surprising that NKG2D, which signals through PI3K in T cells (32), promotes both effector function and memory formation via this protein.…”

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