Duration of TCR Stimulation Determines Costimulatory Requirement of T Cells

Abstract

Current models suggest that T cells that receive only signal-1 through antigenic stimulation of the T cell receptor (TCR) become anergic, but will mount an immune response when a costimulatory signal-2 is provided. Using mice deficient for an important costimulatory molecule, CD28, we show that a transient signal-1 alone, either through infection with an abortively replicating virus, or through injection of viral peptide, anergizes CD8+ T cells, demonstrating the biological relevance of T cell anergy in vivo. However, in the absence of CD28, continued presence of signal-1 alone, either through prolonged viral replication or repeated injection of peptide, prevents the induction of anergy and generates a functional T cell response in vivo.

Dendritic cells infected with recombinant fowlpox virus vectors are potent and long-acting stimulators of transgene-specific class I restricted T lymphocyte activity

“…This difference may be important in vivo since long-term presentation of antigen might be important for an effective CTL response. 15 The limitation of antigen presentation by rFWPV infected DC2.4 cell line was most probably due to loss of viability of the infected cells after 3-5 days. Recombinant protein could still be detected after this time, possibly due to the persistence of the inviable cells in the culture or engulfment by neighbouring cells.…”

“…Peptide binding to MHC class I molecules has been shown to be both rapid and reversible, 14 whereas prolonged exposure to antigen may be necessary for the induction of an efficient T cell response. 15 Moreover, repeated stimulations of T cells with peptide-loaded DC can lead to the emergence of non-cytolytic CD4 + cells which block the activation of fresh T lymphocytes, leading to immune unresponsiveness. 16 It has been known for some time that DNA vaccination using direct injection or gene gun can produce immune responses in experimental animals.…”

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

“…It is interesting to note in this context that IL-2 is the key cytokine needed to overcome T cell anergy [50]. T cells induced in the absence of CD28-mediated costimulation become anergic and fail to proliferate upon re-exposure to antigen; this phenotype may be overcome by addition of exogenous IL-2, which restores T cell proliferation [51]. The data presented here suggest that priming of T cells in the absence of IL-2 may also result in an anergic phenotype.…”

CD4 Help-Independent Induction of Cytotoxic CD8 Cells to Allogeneic P815 Tumor Cells Is Absolutely Dependent on Costimulation

“…Optimal T cell activation is believed to require two signals: ligation of TCR to MHC/peptide complex (signal 1) and costimulation (signal 2). Several reports have described activation of CD8 cells without the need for costimulation, but this requires high dose or persistent Ag exposure and the use of TCR Tg mice (7,(43)(44)(45)(46). In contrast, only in the presence of costimulation can low concentrations of allopeptides induce high CD69 expression, proliferation, and high IL-2 production (43,45).…”