Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

Abstract

Although much is known about the initiation of immune responses, much less is known about what controls the effector phase. CD8+ T cell responses are believed to be programmed in lymph nodes during priming without any further contribution by dendritic cells (DCs) and Ag. In this study, we report the requirement for DCs, Ag, and CD28 costimulation during the effector phase of the CD8+ T cell response. Depleting DCs or blocking CD28 after day 6 of primary influenza A virus infection decreases the virus-specific CD8+ T cell response by inducing apoptosis, and this results in decreased viral clearance. Furthermore, effector CD8+ T cells adoptively transferred during the effector phase fail to expand without DC, CD28 costimulation, and cognate Ag. The absence of costimulation also leads to reduced survival of virus-specific effector cells as they undergo apoptosis mediated by the proapoptotic molecule Bim. Finally, IL-2 treatment restored the effector response in the absence of CD28 costimulation. Thus, in contrast to naive CD8+ T cells, which undergo an initial Ag-independent proliferation, effector CD8+ T cells expanding in the lungs during the effector phase require Ag, CD28 costimulation, and DCs for survival and expansion. These requirements would greatly impair effector responses against viruses and tumors that are known to inhibit DC maturation and in chronic infections and aging where CD28−/− CD8+ T cells accumulate.

Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

“…Thus, these data show that regulation of the proliferative capacity of memory T cells and secondary effectors is controlled at least in part by CD28 signals. These data are in contrast to very early in vitro studies that suggested that memory CD8 + T cells function independently of CD28, and they are supported by more recent in vivo studies in models of viral infection that demonstrated that expansion of secondary effectors was diminished in CTLA-4 Ig-treated mice or was diminished when memory CD8 + T cells were adoptively transferred into CD80/CD86 double-KO hosts (46)(47)(48). These studies showed that, similar to its role in naive T cells, CD28 signaling in memory CD8 + T cells resulted in increased expression of Bcl-xL and increased antigen-specific CD8 + T cell accumulation (47).…”

“…While many studies (including our own) have shown that memory T cells have a reduced requirement for CD28 relative to naive T cells, and in many case can still mediate rejection of an allograft despite CD28 blockade, almost all of these studies reveal that memory T cells are at least somewhat impacted by a loss of CD28 signals [46][47][48]. In this study, we show that both CTLA-4 Ig and anti-CD28 dAb similarly and significantly reduced the expansion and accumulation of donor-reactive CD8 + T cells.…”

Interrupting CD28 costimulation before antigen rechallenge affects CD8+ T‐cell expansion and effector functions during secondary response in mice

“…One caveat with this conclusion is, however, that our experimental read-out, i.e. degranulation and IFN-γ production after antigen-specific restimulation, does not distinguish between an effect of CD28 deficiency or blockade on the differentiation toward a cell ready to express these effector functions, and an effect on the triggering of the response itself, as has been previous noted for global interference with CD28-mediated costimulation in primary influenza infection [31].…”

Absence of CD4+ T cell help generates corrupt CD8+ effector T cells in sarcoma-bearing Swiss mice treated with NLGP vaccine

“…The effect of CD4 depletion was prominent on this particular type of DCs. These DCs communicate to CD8 + T cells by co-stimulation between CD86 and CD28 [42]. CD28 signaling promotes IL-2 production, cell cycle entry and T cell survival [43,44] and we found that NLGP increases CD28 expression on T cells.…”