TY  - JOUR
A1  - Karunakaran, Mohindar M.
A1  - Subramanian, Hariharan
A1  - Jin, Yiming
A1  - Mohammed, Fiyaz
A1  - Kimmel, Brigitte
A1  - Juraske, Claudia
A1  - Starick, Lisa
A1  - Nöhren, Anna
A1  - Länder, Nora
A1  - Willcox, Carrie R.
A1  - Singh, Rohit
A1  - Schamel, Wolfgang W.
A1  - Nikolaev, Viacheslav O.
A1  - Kunzmann, Volker
A1  - Wiemer, Andrew J.
A1  - Willcox, Benjamin E.
A1  - Herrmann, Thomas
T1  - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing
JF  - Nature Communications
N2  - Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members.
KW  - gammadelta T cells
KW  - immunosurveillance
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358179
VL  - 14
ER  - 
TY  - JOUR
A1  - Wilhelm, Martin
A1  - Smetak, Manfred
A1  - Schaefer-Eckart, Kerstin
A1  - Kimmel, Brigitte
A1  - Birkmann, Josef
A1  - Einsele, Hermann
A1  - Kunzmann, Volker
T1  - Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells
JF  - Journal of Translational Medicine
N2  - Background: The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical gamma delta T lymphocytes. 
Methods: Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS (R) device according to the manufacturer's instructions. On average, patients received 2.17 x 10(6)/kg (range 0.9-3.48) γδ T cells with <1% CD4-or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m(2) day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10(6) IU/m(2) IL-2 on day +1 until day +6 for the induction of gamma delta T cell proliferation in vivo. 
Results: This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment. 
Conclusion: This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.
KW  - NK cells
KW  - in vivo cell expansion
KW  - haploidentical γδ T lymphocytes
KW  - adoptive transfer
KW  - CD4(+)
KW  - innate immunity
KW  - stimulation
KW  - acute myeloid-leukemia
KW  - immunotherapy
KW  - cancer
KW  - infusion
KW  - Interleukin-2
KW  - biophosphonate
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117290
VL  - 12
IS  - 45
ER  -