%0 Journal Article
%T Cis interactions between CD2 and its ligands on T cells are required for T cell activation.
%A Li B
%A Lu Y
%A Zhong MC
%A Qian J
%A Li R
%A Davidson D
%A Tang Z
%A Zhu K
%A Argenty J
%A de Peredo AG
%A Malissen B
%A Roncagalli R
%A Veillette A
%J Sci Immunol
%V 7
%N 74
%D 08 2022 5
%M 35930657
%F 30.63
%R 10.1126/sciimmunol.abn6373
%X CD2 is largely described to promote T cell activation when engaged by its ligands, CD48 in mice and CD58 in humans, that are present on antigen-presenting cells (APCs). However, both CD48 and CD58 are also expressed on T cells. By generating new knockout mouse strains lacking CD2 or CD48 in the C57BL/6 background, we determined that whereas CD2 was necessary on T cells for T cell activation, its ligand CD48 was not required on APCs. Rather, CD48 was also needed on T cells. One exception was during cytotoxicity, which required CD48 on T cells and APCs. Fluorescence resonance energy transfer (FRET) studies in nonimmune cells provided evidence that cis interactions between CD2 and CD48 existed within individual cells. CD2-CD48 interactions on T cells enabled more robust T cell receptor (TCR) signals, including protein tyrosine phosphorylation. Using T cells from a CD2 knock-in mouse in which a tag was inserted at the carboxyl terminus of CD2, mass spectrometry analyses revealed that the role of CD2 in T cell activation correlated with its ability to interact with components of the TCR complex and the protein tyrosine kinase Lck. CD2-CD58 provided a similar function in human T cells. Thus, our data imply that T cell-intrinsic cis interactions of CD2 with its ligands are required for TCR signaling and T cell activation. Interactions with ligands on APCs contribute during cytotoxicity.