Alpaca (Vicugna pacos), the first nonprimate species with a phosphoantigen-reactive V gamma 9V delta 2 T cell subset

Fichtner, Alina S.; Karunakaran, Mohindar M.; Gu, Siyi; Boughter, Christopher T.; Borowska, Marta T.; Starick, Lisa; Noehren, Anna; Goebel, Thomas W.; Adams, Erin J. und Herrmann, Thomas (2020): Alpaca (Vicugna pacos), the first nonprimate species with a phosphoantigen-reactive V gamma 9V delta 2 T cell subset. In: Proceedings of the National Academy of Sciences of the United States of America, Bd. 117, Nr. 12: S. 6697-6707

Abstract

V gamma 9V delta 2 T cells are a major gamma delta T cell population in the human blood expressing a characteristic V gamma 9JP rearrangement paired with V delta 2. This cell subset is activated in a TCR-dependent and MHC-unrestricted fashion by so-called phosphoantigens (PAgs). PAgs can be microbial [(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, HMBPP] or endogenous (isopentenyl pyrophosphate, IPP) and PAg sensing depends on the expression of B7-like butyrophilin (BTN3A, CD277) molecules. IPP increases in some transformed or aminobisphosphonate-treated cells, rendering those cells a target for V gamma 9V delta 2 T cells in immunotherapy. Yet, functional V gamma 9V delta 2 T cells have only been described in humans and higher primates. Using a genome-based study, we showed in silico translatable genes encoding V gamma 9, V delta 2, and BTN3 in a few nonprimate mammalian species. Here, with the help of new monoclonal antibodies, we directly identified a T cell population in the alpaca (Vicugna pacos), which responds to PAgs in a BTN3-dependent fashion and shows typical TRGV9- and TRDV2-like rearrangements. T cell receptor (TCR) transductants and BTN3-deficient human 293T cells reconstituted with alpaca or human BTN3 or alpaca/human BTN3 chimeras showed that alpaca V gamma 9V delta 2 TCRs recognize PAg in the context of human and alpaca BTN3. Furthermore, alpaca BTN3 mediates PAg recognition much better than human BTN3A1 alone and this improved functionality mapped to the transmembrane/cytoplasmic part of alpaca BTN3. In summary, we found remarkable similarities but also instructive differences of PAg-recognition by human and alpaca, which help in better understanding the molecular mechanisms controlling the activation of this prominent population of gamma delta T cells.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0027-8424
• Sprache: Englisch