T cell Dissimilarities in B Cell Activating Factor-Deficient Versus B Cell Activating Factor Receptor 3-Deficient Systemic Lupus Erythematosus-Prone NZM 2328 Mice as Contributors to Their Divergent Clinical Outcomes

William Stohl; Ying Wu; Malka Stohl

doi:10.1002/acr2.11712

T cell Dissimilarities in B Cell Activating Factor-Deficient Versus B Cell Activating Factor Receptor 3-Deficient Systemic Lupus Erythematosus-Prone NZM 2328 Mice as Contributors to Their Divergent Clinical Outcomes

ACR Open Rheumatol. 2024 Nov;6(11):756-768. doi: 10.1002/acr2.11712. Epub 2024 Aug 14.

Authors

William Stohl¹, Ying Wu¹, Malka Stohl²

Affiliations

¹ University of Southern California Keck School of Medicine, Los Angeles.
² New York State Psychiatric Institute, New York City.

Abstract

Objective: We assessed the contributions of B cell and T cell subsets to the disparate clinical outcomes in NZM.Baff^-/- and NZM.Br3^-/- mice.

Methods: We assessed in NZM wild-type, NZM.Baff^-/-, and NZM.Br3^-/- mice numbers and percentages of B cells and subsets, T cells and subsets, and in vivo proliferation and survival of forkhead box P3 (Foxp3)⁺ cells by fluorescence-activated cell sorting. Relationships between percentages of Foxp3⁺ cells and numbers of CD19⁺ and CD4⁺ cells were assessed by linear regressions.

Results: In each age and sex cohort, percentages and numbers of CD19⁺ cells were similar in NZM.Baff^-/- and NZM.Br3^-/- mice. Percentages of CD3⁺ and CD4⁺ cells were greater in NZM.Br3^-/- than in NZM.Baff^-/- mice, with the CD4 to CD3 cell ratios being greater in NZM.Br3^-/- than in NZM.Baff^-/- mice and percentages of Foxp3⁺ cells in NZM.Br3^-/- mice being lower than in NZM.Baff^-/- mice. Percentages of Foxp3⁺ cells correlated positively with CD19⁺ cells in NZM.Baff^-/- mice but negatively in NZM.Br3^-/- mice. In vivo proliferation and survival of Foxp3⁺ cells were lower in NZM.Baff^-/- mice than in NZM.Br3^-/- mice.

Conclusion: Differences between NZM.Baff^-/- and NZM.Br3^-/- mice in Foxp3⁺ cells and their relationships with CD19⁺ cells may have more to do with their divergent clinical outcomes than do differences in numbers of B cells. These unexpected findings suggest that B cell activating factor (BAFF)-B cell maturation antigen (BCMA) or BAFF-Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) interactions may help drive development of clinical systemic lupus erythematosus (SLE) even under conditions of considerable B cell depletion. Insufficient blocking of BAFF-BCMA and BAFF-TACI interactions may lie at the heart of incomplete clinical response to BAFF-targeting agents in human SLE.