A genetically regulated SKAP2 switch modulates human T lymphocyte adhesion and migration.
5 affiliations
- 1Institute for Research in Biomedicine, Università della Svizzera italiana , Bellinzona, Switzerland.
- 2Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
- 3Institute of Microbiology, ETH Zürich , Zurich, Switzerland.
- 4INOC - Istituto Nazionale Oncologico Candiolo, IRCCS , Candiolo, Italy.
- 5Department of Oncology, University of Turin, Turin, Italy.
Abstract
Genome-wide association studies investigating autoimmune disorders may reveal previously unrecognized regulators of immune cell functions. A Crohn's disease risk allele was associated with increased expression in T lymphocytes of the adapter protein Src kinase-associated phosphoprotein 2 (SKAP2), whose functional role in these cells is unknown. By analyzing T cells from individuals homozygous for either allelic variant or engineered to modulate SKAP2 endogenous levels, we found that SKAP2 promotes T cell adhesion while restraining migration, acting nonredundantly with its homologue SKAP1. Consistent with such functional differences, SKAP1 and SKAP2 displayed distinct activation-induced regulation as well as unique protein interactomes. Prolonged TCR activation triggered caspase-mediated SKAP2 cleavage, leading to the disassembly of its interactome and enabling a migratory program. Together, these findings identify SKAP2 as a genetically regulated modulator of T cell function whose expression and activity control the balance between adhesion and migration.
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BibTeX
@article{spinella2026genetically,
title = {{A genetically regulated SKAP2 switch modulates human T lymphocyte adhesion and migration.}},
author = {Mara Cetty Spinella and Francesco Gualdrini and Cristina Leoni and Jun Siong Low and Sara Polletti and Amy Kenyon and Samuele Mauri and Veronica Vallelonga and Mehrpouya Mostanfar and Matteo Pecoraro and Chiara Soriani and Roberta Marzi and Elena Grassi and Fabio Bedin and Elena Foli and Niccolò Bianchi and Emina Džafo and Sandra Jovic and Alessandro Cuomo and Simona Rodighiero and David Jarrossay and Federica Sallusto and Gioacchino Natoli and Silvia Monticelli},
journal = {The Journal of experimental medicine},
year = {2026},
month = oct,
doi = {10.1084/jem.20260507},
url = {https://europepmc.org/article/MED/42900686},
note = {CC BY},
}
RIS
TY - JOUR
TI - A genetically regulated SKAP2 switch modulates human T lymphocyte adhesion and migration.
AU - Mara Cetty Spinella
AU - Francesco Gualdrini
AU - Cristina Leoni
AU - Jun Siong Low
AU - Sara Polletti
AU - Amy Kenyon
AU - Samuele Mauri
AU - Veronica Vallelonga
AU - Mehrpouya Mostanfar
AU - Matteo Pecoraro
AU - Chiara Soriani
AU - Roberta Marzi
AU - Elena Grassi
AU - Fabio Bedin
AU - Elena Foli
AU - Niccolò Bianchi
AU - Emina Džafo
AU - Sandra Jovic
AU - Alessandro Cuomo
AU - Simona Rodighiero
AU - David Jarrossay
AU - Federica Sallusto
AU - Gioacchino Natoli
AU - Silvia Monticelli
PY - 2026
DA - 2026/10/20
JO - The Journal of experimental medicine
DO - 10.1084/jem.20260507
UR - https://europepmc.org/article/MED/42900686
AB - Genome-wide association studies investigating autoimmune disorders may reveal previously unrecognized regulators of immune cell functions. A Crohn's disease risk allele was associated with increased expression in T lymphocytes of the adapter protein Src kinase-associated phosphoprotein 2 (SKAP2), whose functional role in these cells is unknown. By analyzing T cells from individuals homozygous for either allelic variant or engineered to modulate SKAP2 endogenous levels, we found that SKAP2 promotes T cell adhesion while restraining migration, acting nonredundantly with its homologue SKAP1. Consistent with such functional differences, SKAP1 and SKAP2 displayed distinct activation-induced regulation as well as unique protein interactomes. Prolonged TCR activation triggered caspase-mediated SKAP2 cleavage, leading to the disassembly of its interactome and enabling a migratory program. Together, these findings identify SKAP2 as a genetically regulated modulator of T cell function whose expression and activity control the balance between adhesion and migration.
SN - 0022-1007
SN - 1540-9538
ER -