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.

Abstract

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