Immunomorphological Analysis of the CD40–CD154 Interaction in T Follicular Helper Cell Lymphoma Emphasizes the Significance of the CD40–CD154 Axis in the Disease

Peripheral T-cell lymphomas (PTCLs) are malignancies of mature T cells with a poor prognosis. Most PTCL cases express follicular T-helper (TFH) cell antigens and are classified as TFH cell lymphoma (TFHL). Contact-dependent signaling between CD40 and its ligand, CD154, is essential for immune functions. CD154 is expressed by activated T cells, while CD40 is found on B cells, follicular and other dendritic cells, macrophages, and stromal cells. Although the CD40–CD154 crosstalk is a key costimulatory pathway in immune responses, data on its role in PTCLs are limited. To explore the role of the CD40–CD154 axis in TFHLs, we conducted an in-depth immunomorphological study of 111 PTCL cases, including 93 TFHL cases. We found that neoplastic T cells in TFHL are consistently CD154-positive. The CD154 expression increased in histologically advanced cases and correlated with the extent of CD40 positivity. We showed that CD154-positive neoplastic T cells recapitulate the intranodal migration of normal TFH cells, disrupting and remodeling each functional compartment, thereby explaining the disease-related immune dysfunction. Our findings indicate that pathological CD40–CD154 interaction is a potential driver mechanism in TFHL and offers a promising target for future therapies.