Jeong-Su Park ^1,2, Jun-Hyeong Kim ^1,2, Won-Chang Soh ^1,2, Na-Young Kim ^1,2, Kyung-Sik Lee ^1,2, Chang-Hyun Kim ^1,2, Ik-Joo Chung ³ , Sunjae Lee ¹, Hye-Ran Kim ^1,2,4 & Chang-Duk Jun ^1,2

¹School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
²Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
³Department of Hematology-Oncology, Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun 58128, Republic of Korea.
⁴Division of Rare and Refractory Cancer, Tumor Immunology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.

Corresponding authors: Correspondence to Hye-Ran Kim or Chang-Duk Jun

Although T cell activation is known to involve the internalization of the T cell antigen receptor (TCR), much less is known regarding the release of TCRs following T cell interaction with cognate antigen-presenting cells. In this study, we examine the physiological mechanisms underlying TCR release following T cell activation. We show that T cell activation results in the shedding of TCRs in T cell microvilli, which involves a combined process of trogocytosis and enzymatic vesiculation, leading to the loss of membrane TCRs and microvilli-associated proteins and lipids. Surprisingly, unlike TCR internalization, this event results in the rapid upregulation of surface TCR expression and metabolic reprogramming of cholesterol and fatty acid synthesis to support cell division and survival. These results demonstrate that TCRs are lost through trogocytic ‘molting’ following T cell activation and highlight this mechanism as an important regulator of clonal expansion.