Lymph node extracellular matrix skews the immune function of human fibroblastic reticular cells

Lymph node (LN) fibroblastic reticular cells (FRCs) are key immunomodulators that regulate adaptive immune responses and provide structural support via extracellular matrix (ECM) production. However, how ECM composition shapes FRC-immune cell interactions remains unclear. Here, we show that ECM composition, specifically collagen type I, laminin α4, or laminin α5, critically determines the immunological status of human FRCs. Bulk RNA sequencing shows that FRCs grown on collagen closely resemble those in native human LN ECM, whereas laminin α4 and α5 differentially skew FRC transcriptomes toward homeostatic/tolerogenic or pro-inflammatory profiles, respectively. These ECM-imprinted FRC states subsequently shape distinct CD4⁺ T cell fates in autologous co-culture assays: laminin α4-FRCs maintain tissue-resident T cells, whereas laminin α5-FRCs selectively enhance effector T cell proliferation. Together, these findings identify ECM as an active instructive signal that, through FRCs, orchestrates immune cell behavior and offers a tunable axis for therapeutic immune modulation.