Extracellular vesicles boost T-cell immune response

As a major component of the immune system, T cells play a critical role in fighting off viral infections. A team led by Prof. Thomas Brocker and Jan Kranich from LMU’s Biomedical Center has demonstrated in a mouse model that so-called extracellular vesicles play an important part in the stimulation of these cells.

Extracellular vesicles are tiny membrane particles that are secreted by cells and play a role in cell-to-cell communication. Using a newly developed method, the scientists were able to show that already activated killer T cells – a subcategory of T cells which directly attack diseased cells – engage intensively with these vesicles. This gives the T cells an extra activating “boost,” which has the effect of promoting their proliferation and increases activation of various genes that are needed to combat the infection.

Ag-dependent stimulation of CD8+ T cells by BMDC-derived EVs

(A) Illustration of experimental setup. At day six of the culture, BMDCs were stimulated with LPS and pulsed with SIINFEKL peptide. PKH26-labeled EVs from BMDCs and injected into H2kbm1 mice that had received in vitro activated OT-I and P14 cells 3 d earlier. One hour later, isolated splenocytes were stained for surface markers, NFATc1 and DRAQ5, and analyzed by IFC. (B) Dot plots show gating of transferred CD90.1+CD45.1 P14 and CD90.1+CD45.1+ OT-I CD8+ T cells with average percentages ±SD (n = 3). The bar graph displays average frequencies ±SD of P14 and OT-I CD8+ T cells in H2kbm1 mice injected with BMDC-derived EVs (+) or noninjected (−). (C) Dot plots show gating of EV+P14 and EV+OT-I CD8+ T cells with average percentages ±SD (n = 3). Bar graph displays average frequencies ±SD of EV+P14 and EV+OT-I CD8+ T cells in H2kbm1 mice injected with BMDC-derived EVs. (D) Representative images depict CD90.1/PKH, CD45.1/PKH, and NFATc1/DRAQ5 overlays of EV+OT-1 and EV+ P14 cells. (E) Representative histograms show the SS of EV+ OT-I and P14 CD8+ T cells with average frequencies ±SD of cells with a SS>1. The bar graphs show the frequencies and the median similarity scores ±SD of EV+, EV OT-I and P14 T cells. Results from OT-I and P14 cells from mice that did not receive EVs are labeled “no EV inj”. Individual mice in different graphs are represented by the same symbol. Results from three mice were pooled from three independent experiments. For statistical significance paired t test was used with *P < 0.05, **P < 0.01, and ***P < 0.001.

Another unexpected finding of the study was that the number of vesicles in the serum decreased after infection, whereas their number increased on T cells in the spleen. From this, the authors concluded that the binding of vesicles to cells is enhanced after an infection.

“Extracellular vesicles essentially function as a ‘danger signal’ for T cells, indicating that the infection has not yet been eliminated,” says Kranich. “We hope to be able to use this discovery in future for therapeutic approaches aimed at strengthening the T cell response to viruses and tumors.”

SourceLudwig-Maximilians-Universität München

Rausch L, Flaskamp L, Ashokkumar A, Trefzer A, Ried C, Buchholz VR, Obst R, Straub T, Brocker T, Kranich J. (2023) Phosphatidylserine-positive extracellular vesicles boost effector CD8+ T cell responses during viral infection. PNAS 120(16):e2210047120. [article]

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