TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation

Jonathan D. Worboys, Katherine N. Vowell, Roseanna K. Hare, Ashley R. Ambrose, Margherita Bertuzzi, Michael A. Conner, Florence P. Patel, William H. Zammit, Judit Gali-Moya, Khodor S. Hazime, Katherine L. Jones, Camille Rey, Stipan Jonjic, Tihana Lenac Rovis, Gillian M. Tannahill, Gabriela Dos Santos Cruz De Matos, Jeremy D. Waight and Daniel M. Davis ()
Additional contact information
Jonathan D. Worboys: University of Manchester
Katherine N. Vowell: GlaxoSmithKline
Roseanna K. Hare: University of Manchester
Ashley R. Ambrose: University of Manchester
Margherita Bertuzzi: University of Manchester
Michael A. Conner: GlaxoSmithKline
Florence P. Patel: GlaxoSmithKline
William H. Zammit: University of Manchester
Judit Gali-Moya: University of Manchester
Khodor S. Hazime: University of Manchester
Katherine L. Jones: University of Manchester
Camille Rey: University of Manchester
Stipan Jonjic: University of Rijeka
Tihana Lenac Rovis: University of Rijeka
Gillian M. Tannahill: GlaxoSmithKline
Gabriela Dos Santos Cruz De Matos: GlaxoSmithKline
Jeremy D. Waight: GlaxoSmithKline
Daniel M. Davis: University of Manchester

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.

Date: 2023
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DOI: 10.1038/s41467-023-40755-3

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