Memory CD8+ T Cells Require CD28 Costimulation

Abstract

CD8+ T cells are a critical component of the adaptive immune response against infections and tumors. A current paradigm in immunology is that naive CD8+ T cells require CD28 costimulation, whereas memory CD8+ T cells do not. We show here, however, that during viral infections of mice, costimulation is required in vivo for the reactivation of memory CD8+ T cells. In the absence of CD28 costimulation, secondary CD8+ T cell responses are greatly reduced and this impairs viral clearance. The failure of CD8+ T cells to expand in the absence of CD28 costimulation is CD4+ T cell help independent and is accompanied by a failure to down-regulate Bcl-2 and by cell cycle arrest. This requirement for CD28 costimulation was shown in both influenza A and HSV infections. Thus, contrary to current dogma, memory CD8+ T cells require CD28 costimulation to generate maximal secondary responses against pathogens. Importantly, this CD28 requirement was shown in the context of real infections were multiple other cytokines and costimulators may be up-regulated. Our findings have important implications for pathogens, such as HIV and measles virus, and tumors that evade the immune response by failing to provide CD28 costimulation. These findings also raise questions about the efficacy of CD8+ T cell-based vaccines against such pathogens and tumors.

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

“…This suggests that the virus-specific CD8 + T cells during the effector phase need both IL-15 and costimulation signals as prosurvival factors. Our current study reveals an unappreciated role of CD28 costimulation during the CD8 + T cell effector phase and may explain the need for CD28 costimulation recently described by us and others for the generation of optimal secondary responses from memory CD4 + and CD8 + T cells (25,47,48). In addition to this, we show that the absence of CD28 costimulation and antigenic signals at the effector phase has an impact on viral clearance, as our studies show that there is decreased viral clearance in the absence of DCs at the effector stage most likely due to the reduced numbers of virus-specific CD8 + T cells.…”

“…RNA was isolated by the Qiagen RNeasy kit (Qiagen). The isolated RNA was then used for cDNA synthesis, and virus was measured by real-time PCR as previously described (25). Viral loads of the experimental samples were calculated using a standard curve of a stock PR8 virus with known concentration of virus 50% tissue culture-infective dose per milliliter.…”

CD27 costimulation contributes substantially to the expansion of functional memory CD8+T cells after peptide immunization

“…Our finding that memory T-cell reactivation by either anti-CD40 or sCD70 is dependent on CD80/86 confirms previous studies showing that CD28/80/86 are necessary for memory CD8 + T-cell responses after infection with vaccinia, influenza, or lymphocytic choriomeningitis virus (LCMV) and for memory CD4 + T-cell expansion and IL-2 secretion after rechallenge with antigenic protein [24][25][26][27]. However, whether CD27 similarly plays a role during memory T-cell activation has been less clear; many studies that sought to address this question have made use of CD27-deficient or CD70-overexpressing mice in which interpretation of the memory CD8 + T-cell response is complicated by the impact of CD27/CD70 signals on CD8 + T-cell priming/imprinting and memory differentiation [6,9,12,41,42].…”

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…While some studies suggest that memory T cells do not require costimulation for reactivation, others have reported that costimulation remains necessary for their recall activation and expansion in vivo (40)(41)(42)(43)(44)(45). By carefully tracking endogenous donor-specific T cells using the IFN-γ ELISPOT assay as well as with fluorescently labeled 2W:I-A b and OVA:K b multimers, we observed that CTLA4-Ig was able to prevent the expansion of donor-specific T cells in sensitized mice.…”