Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Rho GTPases, such as RhoA, are emerging 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. Our laboratory previously identified a role for ROCK2 in the differentiation of TH17 cells through the phosphorylation of IRF4. This ROCK2-pIRF4 pathway drives the production of key effector cytokines, such as IL-21, and is deregulated in several autoimmune models. While previous studies have focused on the role of ROCK2 in the T cell compartment, ROCK2 is expressed in other immune cell types, including B cells, leading us to hypothesize that ROCK2 may play a broad role in immunoregulation and T-B collaborations.
Methods: To assess the role of B-cell ROCK2 in T cell-dependent responses, WT mice or mice with B cell-specific deletion of ROCK2 were immunized with a T-dependent antigen and differentiation of germinal center (GC) B cells and plasmablasts/plasma cells (PB/PCs) was monitored by FACS. The molecular mechanisms employed by ROCK2 to promote B cell differentiation was further examined by FACS-sorting B cell populations from spleens of immunized mice followed by qPCR and immunoblot analyses. Total and antigen-specific antibody responses were assessed by ELISA.
Results: We found that ROCK2 is activated in GC B cells and in PB/PCs following immunization and that ROCK2 activity is also induced in vitro upon stimulation with T-cell derived signals such as aCD40 and IL-21. Mice with B cell-specific deletion of ROCK2 exhibited no abnormalities in their mature B cell compartments at baseline, yet showed marked decreases in total and antigen-specific antibody titers in response to immunization with a TD antigen. These decreased humoral responses corresponded with diminished germinal center formation and maintenance following antigen challenge. Residual germinal centers in ROCK2-deficient mice revealed skewed frequencies of GC subpopulations, reduced proliferation, and attenuated class switching to IgG1.
Conclusion: Our study demonstrates that ROCK2 is activated in B cells following immunization with a TD antigen and is required for optimal GC maintenance and function. These findings thus uncover a previously unknown B cell-intrinsic role for ROCK2 in promoting humoral responses and further support the notion that targeting ROCK2 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, Ye C, Flores-Castro D, Gupta S, Manni M, Chinenov Y, Pannellini T, Liao JK, Pernis AB. The Rho Kinase Family Member, ROCK2, Promotes Germinal Center Responses and Is Required for Optimal Humoral Immunity [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/the-rho-kinase-family-member-rock2-promotes-germinal-center-responses-and-is-required-for-optimal-humoral-immunity/. Accessed August 9, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-rho-kinase-family-member-rock2-promotes-germinal-center-responses-and-is-required-for-optimal-humoral-immunity/