Cytokine-Mediated Programmed Proliferation of Virus-Specific CD8+ Memory T Cells

Abstract

Summary During infection, CD8+ T cells not only respond to antigenic signals through their T cell receptor (TCR), but also incorporate inflammatory signals from cytokines produced in the local infected microenvironment. Transient TCR-mediated stimulation will result in programmed proliferation that continues despite removal of the antigenic stimulus, but it remains unclear whether brief exposure to specific cytokines will elicit similar effects. Here, we have demonstrated that brief stimulation of memory T cells with interleukin-12 (IL-12) and IL-18 resulted in tightly regulated programmed proliferation in addition to acquisition of enhanced virus-specific cytokine production and cytolytic activity. CD8+ T cells briefly exposed to IL-12+IL-18 in vitro showed improved antiviral activity in vivo as demonstrated by increased proliferation and reduced viremia. These results indicate that even transitory exposure to inflammatory cytokines may provide a selective advantage to infiltrating CD8+ T cells by triggering a developmental program that is initiated prior to direct contact with virus-infected cells.

Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection

“…Taken together, our data showing increased PD-1 expression selectively in Fut7 −/− T cells in an otherwise normal environment suggest that T-cell exhaustion is a T cell-intrinsic phenomenon that is largely independent of antigen load or persistence. Recent studies show that a pathogen-specific inflammatory milieu enhances proliferative and effector capacity of memory T cells (31)(32)(33). Our data further suggest that T-cell exhaustion results from the inability of the T cells to migrate to the target organ, leading us to speculate that T cells activated in secondary lymphoid organs receive some further "instruction" in the target organ to become fully activated, mediate effector function, generate effective memory, and escape exhaustion.…”

Inflammatory IL-15 is required for optimal memory T cell responses

“…Our data, obtained with several experimental approaches, clearly demonstrate that, while IL-15 is involved in regulating memory CD8 + T cell proliferation over the course of viral infection in vivo, blocking IL-2 had no effect on the capacity of bystander viral infection to induce cell-cycle entry of memory CD8 + T cells. While the regulation of cell-cycle entry was entirely regulated by IL-15 following bystander infection with the viral model used in this study, it remains possible that other infections induce similar responses through mechanisms involving other cytokines (15). This suggests that specific inflammatory milieux induced over the course of different infections may regulate the proliferation of memory CD8 + T cells through different mechanisms.…”

“…+ T cells in a bystander manner (13)(14)(15)(16). In particular, a recent study demonstrated that in vitro treatment with IL-12 and IL-18 leads to the proliferation of memory CD8 + T cells in an IL-2-dependent manner and suggested that this may be important in protection from reinfection (15).…”

“…In particular, a recent study demonstrated that in vitro treatment with IL-12 and IL-18 leads to the proliferation of memory CD8 + T cells in an IL-2-dependent manner and suggested that this may be important in protection from reinfection (15). Additionally, Sprent and colleagues showed that infection with viruses (16) or injection of adjuvants (17) can stimulate proliferation of memory-phenotype CD8 + T cells generated through homeostatic proliferation in lymphopenic adult thymectomized mice.…”

“…In addition, other cytokines may be involved in regulating the proliferative capacity of memory CD8 + T cells, as recent in vitro data have demonstrated a role for IL-12 and IL-18 in the induction of memory CD8 + T cell proliferation. The mechanism regulating proliferation of memory CD8 + T cells following IL-12/IL-18 stimulation in vitro was dependent on IL-2 production by CD4 + T cells (15). Our data, obtained with several experimental approaches, clearly demonstrate that, while IL-15 is involved in regulating memory CD8 + T cell proliferation over the course of viral infection in vivo, blocking IL-2 had no effect on the capacity of bystander viral infection to induce cell-cycle entry of memory CD8 + T cells.…”