High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

Utzschneider, Daniel T.; Alfei, Francesca; Roelli, Patrick; Barras, David; Chennupati, Vijaykumar; Darbre, Stéphanie; Delorenzi, Mauro; Pinschewer, Daniel D.; Zehn, Dietmar

doi:10.1084/jem.20150598

Cited by 136 publications

(138 citation statements)

References 59 publications

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“…To exclude a sole OT-1-dependent phenomenon, we reversed the strategy and used the recently described gp33C6 low-affinity APL for P14 T cells (Utzschneider et al., 2016). We transferred OT-1 memory and naive P14 T cells into naive B6 mice and infected them with Listeria expressing Ova and wild-type (Lm-gp33-N4) or the low-affinity APL gp33C6 (Lm-gp33C6-N4).…”

Section: Resultsmentioning

confidence: 99%

A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

et al. 2016

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SummaryMany infections are caused by pathogens that are similar, but not identical, to previously encountered viruses, bacteria, or vaccines. In such re-infections, pathogens introduce known antigens, which are recognized by memory T cells and new antigens that activate naive T cells. How preexisting memory T cells impact the repertoire of T cells responding to new antigens is still largely unknown. We demonstrate that even a minimum epitope overlap between infections strongly increases the activation threshold and narrows the diversity of T cells recruited in response to new antigens. Thus, minimal cross-reactivity between infections can significantly impact the outcome of a subsequent immune response. Interestingly, we found that non-transferrable memory T cells are most effective in raising the activation threshold. Our findings have implications for designing vaccines and suggest that vaccines meant to target low-affinity T cells are less effective when they contain a strong CD8 T cell epitope that has previously been encountered.

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Section: Resultsmentioning

confidence: 99%

A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

et al. 2016

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“…This minor subpopulation contains the ability to differentiate into TCF7 − effector T cells, which mediate viral control, as well as TCF7 + memory-like T cells that are capable of self-renewal. The maintenance of the proliferative capacity in chronic infections has been shown to be uncoupled from the phenotype of a T cell population (Utzschneider et al, 2016a). This presents the possibility that the same T cell program of gene expression important for immunity to an acute reinfection is continuously maintained and active during a chronic infection (Speiser et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1

et al. 2018

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SUMMARY Immunity following an acutely resolved infection or the long-term equipoise of chronic viral infections often depends on the maintenance of antigen-specific CD8+ T cells, yet the ongoing transcriptional requirements of these cells remain unclear. We show that active and continuous programming by FOXO1 is required for the functional maintenance of a memory population. Upon Foxo1 deletion following resolution of an infection, memory cells rapidly lost their characteristic gene expression, gradually declined in number, and were impaired in self-renewal. This was extended to chronic infections, as a loss of FOXO1 during a persistent viral infection led to a rapid decline of the TCF7 (a.k.a. TCF1)-expressing memory-like subset of CD8+ T cells. We further establish FOXO1 regulation as a characteristic of human memory CD8+ T cells. Overall, we show that the molecular and functional longevity of a memory T cell population is actively maintained by the transcription factor FOXO1.

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“…Collectively, these data suggest that GD2 CART cell depletion was more dependent on the density of CAR on the cell surface than on the affinity of the CAR itself. In fact, it was recently reported that acquisition of an exhausted phenotype by T cells was determined more by the frequency of T cell receptor (TCR) engagement than with the strength of TCR engagement 20 . Recently, Tanaka et al.…”

Section: Discussionmentioning

confidence: 99%

Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2

et al. 2017

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Chimeric antigen receptors (CAR) and bispecific antibodies (BsAb) are two powerful immunotherapy approaches for retargeting lymphocytes toward cancer cells. Despite their success in lymphoblastic leukemia, solid tumors have been more recalcitrant. Identifying therapeutic barriers facing CAR-modified (CART) or BsAb-redirected T (BsAb-T) cells should facilitate their clinical translation to solid tumors. Novel lentiviral vectors containing low-affinity or high-affinity 4-1BB second-generation anti-GD2 (disialoganglioside) CARs were built to achieve efficient T cell transduction. The humanized anti-GD2 × CD3 BsAb using the IgG-scFv platform was described previously. CART and BsAb-engaged T cells were tested for viability, proliferation, and activation/exhaustion marker expression, and in vitro cytotoxicity against GD2(+) tumor cells. The antitumor effect of CAR-grafted and BsAb-T cells was compared in a human melanoma xenograft model. The majority of high CAR density T cells were depleted upon exposure to GD2(+) target cells while the BsAb-T cells survived. The in vitro cytotoxicity of the surviving CART cells was inferior to that of the BsAb-T cells. Using low-affinity CARs, inclusion of the 4-1BB co-stimulatory domain or exclusion of a co-stimulatory domain, or blocking PD1 did not prevent CART cell depletion. Both CART cells and BsAb-T cells penetrated established subcutaneous human melanoma xenografts; while both induced tumor regression, BsAb was more efficient. The fate of T cells activated by BsAb differs substantially from that by CAR, translating into a more robust antitumor effect both in vitro and in vivo.

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High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

Abstract: Using recombinant antigen variant-expressing chronic LCMV strains, Zehn and colleagues showed that amount rather than antigen strength is a key determinant of inducing a chronic infection phenotype in T cells.

Cited by 136 publications

References 59 publications

A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1

Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2

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