Innate Immunity Together with Duration of Antigen Persistence Regulate Effector T Cell Induction

Activation of naive T cells by quiescent APCs results in tolerance through deletion and anergy. The underlying basis for these distinct fates is unclear. Using clone 4 TCR transgenic animals as a source of naive CD8 T cells, we examined the requirements for peripheral deletion in vivo. Our results demonstrate that independent of the amount of Ag used for stimulation, a single dose was insufficient to achieve complete clonal deletion. Instead, further antigenic exposure was required to completely eliminate all of the activated T cells. Additionally, consecutive stimulations with low doses of Ag were highly effective in promoting deletion. In contrast, although stimulation with high doses of Ag initially led to the apoptosis of many of the activated T cells, it induced hyporesponsiveness in a portion of the responding cells, thereby sparing them from further activation and deletion. These data explain why some conditions promote tolerance through clonal deletion whereas others promote anergy. Furthermore, these data provide a framework to devise protocols for effective deletion of potentially autoreactive T cells.

Section: Phenotype Of Peptide-tolerized Clone 4 T Cells In Vivosupporting

confidence: 82%

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Redmond

Marincek

Sherman

2005

“…Although the mechanisms controlling this process are not fully understood, it is hypothesized that a negative feedback process exists in which the DCs become targets of the CTL that they prime (8 -10). Recent studies demonstrated that enhancement of DC survival augmented T cell priming supporting the idea that prolonging Ag presentation by the DC vaccine may be advantageous (11)(12)(13)(14)(15). Furthermore, a report by Medema et al (16) demonstrated that activation of DCs by CD40L or LPS rendered DCs resistant to the in vitro cytotoxic activity of CTLs.…”

Section: T He Cd8mentioning

confidence: 81%

Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL

Luketic¹,

Delanghe²,

Sobol

et al. 2007

123

Despite the potency of dendritic cells (DCs) as a vaccine carrier, they are short-lived and sensitive to CTL-mediated elimination. Thus, it is believed that the longevity of Ag presentation by peptide-pulsed DC is limited in vivo. Surprisingly, however, we found that although the majority of injected DCs disappeared from the draining lymph nodes within 7 days, Ag presentation persisted for at least 14 days following DC immunization. This prolonged Ag presentation was not mediated by the remaining injected DCs or through Ag transfer to endogenous APCs. We provide evidence that exosomes released by DCs might be responsible for the persistence of Ag presentation. Functional exosomes could be recovered from the draining lymph nodes of C57BL/6 mice following DC vaccination and, in contrast to DCs, T cell stimulation by exosomes in vivo was not affected by the presence of CTL. Our findings demonstrate that Ag presentation following delivery of DC vaccines persists for longer than expected and indicate that the exosome may play a previously unrecognized role in Ag presentation following DC vaccination. Furthermore, our study reinforces the application of exosomes as a vaccination platform and suggests that exosome-based vaccines may be advantageous for booster immunizations due to their resistance to CTL.

“…However, there is also data that CD8 + T cell expansion is correlated with the continued duration of TCR stimulation in the context of both infections and sterile vaccinations (13)(14)(15)(16)(17)(18)(19)(20)(21). The reason for this discrepancy is currently unclear and cannot be explained by differences of protocol, experimental systems or availability of help or inflammation.…”

Section: T Cell Receptor-mediated Recognition Of Antigenic Peptidesmentioning

confidence: 83%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.