Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Follicular helper T (TFH) cells promote humoral responses and serve as a limiting factor for the selection of high affinity germinal center B cells. TFH cell numbers need to be tightly regulated, and TFH cell expansion has been associated with autoimmune diseases including SLE. Rho-associated kinases (ROCKs), ROCK1 and ROCK2, are major downstream effectors of the small GTPase RhoA. The ROCKs regulate both gene expression and cytoskeletal reorganization. Increased ROCK activation has been observed in autoimmune disease both in mice and humans, and ROCK inhibition ameliorates autoimmunity in murine models. However, the underlying molecular and cellular mechanisms by which the ROCKs affect autoimmune disease are currently unknown. Here we investigated the role of ROCK2 in TFH cell expansion under physiological conditions and in autoimmunity by employing mice lacking DEF6 and SWAP-70, which exhibit aberrant ROCK activation, accumulation of TFH cells, and spontaneously develop a lupus-like disease.
Methods: Mice lacking ROCK2 in T cells were generated by crossing CD4cre mice with ROCK2flox/flox mice. The TFH cell compartment was assessed in CD4creROCK2flox/flox mice by immunizing with a T-dependent antigen. To evaluate the effect of T-cell ROCK2 on autoimmune disease CD4creROCK2flox/flox mice were crossed with Def6trap/trapSwap-70-/- mice (DKO mice), which develop a lupus-like disease primarily in females. Flow cytometry analysis and ELISAs were used to assess TFH cell expansion and autoantibody production.
Results: The absence of ROCK2 in T cells did not lead to any abnormality in the frequencies or activation state of the T cell compartment at baseline. Lack of T cell ROCK2, however, resulted in a significant decrease in TFH cell formation upon immunization with a T-dependent antigen. This was associated with a reduction in germinal center B cell and plasma cell formation suggesting that T-cell ROCK2 is essential for T-dependent immune responses. To evaluate the contribution of T-cell ROCK2 to TFH cell formation in autoimmunity, we analyzed CD4creROCK2flox/flox Def6trap/trapSwap-70-/- mice (ROCK2ΔT DKO) mice. Upon deletion of T cell ROCK2, the spontaneous increase in TFH cells observed in DKO mice was significantly reduced. This was associated with decreased GC B cells, plasma cell numbers, and diminished anti-dsDNA autoantibody levels.
Conclusion: Our current study indicates that ROCK2 regulates TFH cells both during T-dependent immune responses as well as in autoimmune settings further supporting a role for ROCK inhibition as a potential treatment for SLE and other autoimmune diseases that exhibit dysregulation in TFH cells.
To cite this abstract in AMA style:Yi W, Gupta S, Weng CH, Chinenov Y, Liao JK, Pernis AB. Regulation of Follicular Helper T (TFH) Cells By ROCK2 (Rho-associated coiled-coil containing protein kinase 2) [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/regulation-of-follicular-helper-t-tfh-cells-by-rock2-rho-associated-coiled-coil-containing-protein-kinase-2/. Accessed March 20, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-follicular-helper-t-tfh-cells-by-rock2-rho-associated-coiled-coil-containing-protein-kinase-2/