Abstract A012: USP11 links germinal center B-cell fate to adaptive immune crosstalk in immunized mice
Anirban Roychowdhury, Forum Kayastha, Mark A. Subler, Madelyn R. Lorenz, Won Sok. Lee, Nahid Nanaji, Jolene J. Windle, Bandish Kapadia, Ronald B. GartenhausAbstract
Introduction:
Germinal center B-cell responses require precise control of differentiation to balance plasma cell output and memory formation. Despite substantial insight into the transcriptional regulation of these processes, the role of post-translational control remains poorly understood. Disruption of B-cell developmental programs contributes to germinal center-derived lymphoid malignancies, and identifying these regulatory mechanisms is of significant clinical relevance. Ubiquitin Specific Peptidase 11 (USP11) has been implicated in lymphoid malignancies, including diffuse large B-cell lymphoma and T-cell acute lymphoblastic leukemia, and more recently in the survival of splenic marginal zone B cells. However, whether USP11 governs B-cell fate during physiological immune responses currently remains unknown. To address this gap, we used complementary B cell-specific conditional mouse models together with single-cell transcriptomic profiling to examine whether USP11 acts within B cells to control developmental pace and lineage choice upon immunization.
Methods:
Splenocytes from immunized USP11 loss-of-function, gain-of-function, and matched Cd19-Cre− control mice were profiled by 5′ scRNA-seq. Splenic B-cell states were defined using specific signature frameworks and orthogonally confirmed by multiplex immunohistochemistry. Integrated differential expression, enrichment, trajectory, pseudotime, and intercellular signaling analyses were then applied to evaluate cell-intrinsic and microenvironmental effects of USP11 perturbation.
Results:
USP11 altered transcriptional programs related to cellular metabolism, protein synthesis capacity, and cytokine response pathways. Loss of Usp11 accelerated the B-cell maturation axis and more robust terminally differentiated plasma states. By contrast, enforced USP11 expression restrained progression toward terminal differentiation and favored memory-skewed states. These B cell-intrinsic effects were accompanied by broader remodeling of the immune milieu, with USP11 overexpression favoring predicted B-T cell interaction networks and more differentiated T-cell states, whereas USP11 deficiency was linked to weaker co-stimulatory programs and a relative enrichment of less differentiated T-cell phenotypes.
Conclusions:
USP11 appears to shape germinal center output by influencing B-cell developmental trajectories and immune interactions within the splenic environment. These findings suggest a role for USP11-regulated programs in germinal center B cell biology and provide insight into processes associated with lymphoma development.
Citation Format:
Anirban Roychowdhury, Forum Kayastha, Mark A. Subler, Madelyn R. Lorenz, Won Sok. Lee, Nahid Nanaji, Jolene J. Windle, Bandish Kapadia, Ronald B. Gartenhaus. USP11 links germinal center B-cell fate to adaptive immune crosstalk in immunized mice [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A012.