Differential expression of T(HELPER)1 cytokines upon antigen stimulation predicts ex vivo proliferative potential and cytokine production of virus-specific T cells following re-stimulation
TRANSPLANT INFECTIOUS DISEASE
Authors: Feucht, J.; Leibold, J.; Halder, A.; Kayser, S.; Hartl, L.; Rammensee, H. -G.; Handgretinger, R.; Feuchtinger, T.
IntroductionCytomegalovirus (CMV) and human adenovirus (ADV) infections are causes of morbidity after stem cell transplantation. Antigen (Ag)-specific T cells are essential for the control of viral infections. However, in vivo expansion potential of T-cell subpopulations is hardly predictable in humans. Furthermore, ex vivo identification of human T cells with repopulating capacity for adoptive T-cell transfer has been difficult. MethodsWe analyzed Ag-specific T-cell populations, subdivided according to the expression of different T(HELPER-)1 (Th1) cytokines. Isolation by flow cytometry was based on interferon-gamma (IFN)-, interleukin (IL)-2, or tumor necrosis factor-alpha (TNF-) secretion of T cells after ex vivo stimulation with the Ags hexon (for ADV) and pp65 (for CMV). Isolated T cells were expanded and examined for functional characteristics, expansion/differentiation potential, and naive, effector memory, central memory, and late effector phenotypes. ResultsIsolation based on IFN- production provides a T-cell population with a mixture of early, central memory, and effector memory T cells, high expansion potential, and effective cytokine production. Selection of T cells with Ag-specific expression of IL-2 or TNF-, however, results in a T-cell population with reduced proliferation and lower effector potential after expansion. ConclusionWe conclude that the exclusive secretion of IFN- in the human antiviral T-cell responses preferentially leads to higher repopulation capacities of antiviral T cells, compared to IL-2 or TNF- secreting T-cell populations.
High-intensity interval training in allogeneic adoptive T-cell immunotherapy - a big HIT?
JOURNAL OF TRANSLATIONAL MEDICINE
Authors: Heinemann, Nele Carolin; Tischer-Zimmermann, Sabine; Wittke, Torge Christian; Eigendorf, Julian; Kerling, Arno; Framke, Theodor; Melk, Anette; Heuft, Hans-Gert; Blasczyk, Rainer; Maecker-Kolhoff, Britta; Eiz-Vesper, Britta
Background Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor's peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach. Methods This pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors' cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein-Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) gamma cytokine secretion assay and virus-derived overlapping peptide pools. Results HIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies. Conclusion This study demonstrates that exercise before T-cell donation has a beneficial effect on the donor's cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.