Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Rho GTPases, such as RhoA, have emerged as important regulators of lymphocyte biology owing to their ability to be rapidly activated downstream of a broad range of signals. Two of the major effectors of RhoA signaling are the Rho Kinases (ROCKs), ROCK1 and ROCK2, a pair of serine-threonine kinases that have been previously implicated in the control of cell adhesion, migration, proliferation/survival, and gene expression. Despite the fundamental reliance of T and B cells on these processes, the precise involvement of the ROCKs in lymphocyte biology is yet to be elucidated. Here, we investigate the contribution of ROCK1 to B cell development and differentiation following immunization with a T-dependent antigen.
Methods: To assess the roles of B cell ROCK1 in T cell-dependent responses, mice with B cell-specific deletions of ROCK1 (CD23-Cre.Rock1flox/flox and Cγ-Cre.Rock1flox/flox mice) were immunized with a T-dependent antigen. Rock1flox/flox mice were also immunized as a control for this study. The differentiation of germinal center (GC) B cells and plasmablast/plasma cells (PB/PCs) was monitored by FACS at various timepoints following immunization. Total and antigen-specific antibody responses were also assessed by ELISA. The molecular mechanisms employed by ROCK1 to promote B cell differentiation were further examined by FACS-sorting B cell populations from spleens of immunized mice followed by RNA-sequencing analyses.
Results: We found that ROCK1 is expressed and activated in splenic B cells. Mice with B cell-specific deletion of ROCK1 showed marked reductions in total and antigen-specific antibody responses following immunization. These decreased humoral responses corresponded with impaired formation and maintenance of antigen-specific GC B cells and PB/PCs following immunization in the ROCK1-deficient mice. Through next generation sequencing, we have furthermore identified a ROCK1-regulated transcriptional program that supports the phenotype of GC B cells.
Conclusion: Our study demonstrates that ROCK1 is activated in B cells and is required for the optimal development of mature B cell populations at baseline and for efficient GC responses following immunization. These findings thus uncover previously unknown B cell-specific roles for ROCK1 in promoting humoral responses and suggests that targeting ROCK1 activity may provide therapeutic benefit for the treatment of diseases marked by aberrant B cell responses.
To cite this abstract in AMA style:Ricker E, Flores-Castro D, Gupta S, Cheng A, Chinenov Y, Pannellini T, Kim Y, Pernis A. B Cell ROCK1 Promotes Germinal Center Responses and Is Required for Optimal Humoral Immunity [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/b-cell-rock1-promotes-germinal-center-responses-and-is-required-for-optimal-humoral-immunity/. Accessed June 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-rock1-promotes-germinal-center-responses-and-is-required-for-optimal-humoral-immunity/