2011 - BSS 2011 Symposium

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Moderated Posters 1

5.15 - Impaired IL2 signaling promotes CD4-mediated antiviral CD8+ T cell response

Presenter: Michael, Schmück, Berlin, Germany
Authors: Michael Schmück2,3, Ben Hammoud2, Annika Fischer2, Si-Hong Luu3, Hans-Dieter Volk2,3, Petra Reinke1,3

Impaired IL2 signaling promotes CD4-mediated antiviral CD8+ T cell response

Michael Schmück2,3, Ben Hammoud2, Annika Fischer2, Si-Hong Luu3, Hans-Dieter Volk2,3, Petra Reinke1,3

1Department of Nephrology / Intensive Care, Charité University Medicine Berlin; 2Institute of Medical Immunology; 3Berlin-Brandenburg Center for Regenerative Therapies; Germany

Viral infections like HCMV cause frequent and severe complications in solid organ transplant (SOT) recipients. We recently demonstrated a new approach using autologous HCMV specific T-cell therapy for a ganciclovir-resistant lung-transplanted patient who was under long-term mechanical ventilation. We were able to generate successfully HCMV-specific T-cells from this severely ill patient. The adoptively transferred T cells rapidly cleared viral infection and patient recovered within days from ventilation that was necessary over months before. After full recovery, the patient was released from the clinic 3 weeks after T-cell infusion. After 7 weeks, the patient relapsed unexpectedly. According to the experimental data this might have been due to the late differentiation phenotype of the infused T cells and therefore their insufficient longevity in vivo. Late differentiated effector/memory T cells have powerful effector function but are not able to establish long-lasting protective memory due to diminished proliferative potential. Hence, the aim is to generate T-cell lines capable of strong engraftment after adoptive transfer. We used a peptide-based protocol to generate virus-specific CD4+/8+ T-cell lines from PBMC using the MACS IFNg-secretion assay. In this report, we show that the partial inhibition of the IL2 signaling pathway during the expansion-phase of the culture strongly increases antiviral responses and, most importantly, maintain an early effector/memory phenotype. The T-cell lines show prolonged expression of CD127, CCR7 and CD62L. Notably, the inhibition significantly balanced the CD4 / CD8 ratio, what consecutively entails to a superior antiviral CD8 response in vitro. The generated T-cell lines showed dose-dependent specific lysis of peptide loaded targets and enhanced cytokine secretion. This approach might be a potent strategy to generate antigen-specific T cells with a high functional capacity and robust long-term persistence in vivo.

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