AUTHOR=Campbell Adana-Christine , Stull-Lane Annica R. , Baik Jung Eun , Sarker Ananta , Shin Jinyeon , Ashokan Gopika , Park Hyeung Ju , Pollack Bracha L. , Pakkerakari Pradhi , Parisotto Yollanda Franco , Roberts Arielle , Brown Chrysothemis C. , Mehrara Babak J. , Kataru Raghu P. 

TITLE=Lymphedema pathogenesis involves antigen-driven expansion of CD4+ T cells in skin

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1620571

DOI=10.3389/fimmu.2025.1620571

ISSN=1664-3224

ABSTRACT=IntroductionLymphedema, a progressive condition involving unresolved swelling and inflammation, affects as many as 1 in 1000 Americans. Although CD4+ T cells are implicated in the chronic inflammatory process, antigen-specific responses are understudied.MethodsUsing high-throughput sequencing, we studied the T cell receptors (TCRs) of CD4+ T cells in paired normal and lymphedema skin biopsies of 11 patients. We also employed in vitro studies using human samples and cells from a lymphedema mouse model.ResultsTarget epitopes of the TCRs, including the antigen insulin, were identified. Clonality was significantly higher in lymphedema samples than in controls, both in human samples and a mouse model of the disease. In vitro studies using human samples and a lymphedema mouse model demonstrated increased activated memory T cell responses specific to the antigen insulin compared with the control.DiscussionOur study highlights an oligoclonal expansion of CD4+ T cells in lymphedema and supports insulin as a probable antigen driving T cell responses. These findings can help inform more precise therapeutic targets for the development of better therapies and preventative tools to combat lymphedema progression.