Background/Purpose: T follicular helper (Tfh) cells are a specialized CD4⁺ T cell subset which can help B cells in the germinal center (GC) to drive B cell differentiation and antibody production. Dysregulation of Tfh and/or B cells often leads to breakdown in tolerance and development of autoimmunity. NF-κB inducing kinase (NIK) regulates immune cell signaling downstream of a subset of the tumor necrosis factor superfamily receptors including BAFFR, CD40, OX40, lymphotoxin receptor and RANK. It has been demonstrated that NIK is critical for B cell responses, but it is less clear how NIK regulates Tfh cell biology.

To investigate the role of NIK in CD70/CD27 signaling in the context of human Tfh cell differentiation and function by utilization of a small molecule NIK inhibitor in vitro and in vivo.

Methods: Human Tfh cells or plasma cells were generated with various ligands stimulating NIK induced NF-κB signaling. The proteolysis of p100 into p52 was examined by western blot to evaluate NIK activation. We performed flow cytometry, quantitative PCR, and ELISA to assess how NIK activation and/or inhibition impacted on Tfh development and plasma cell differentiation. B-T co-culture and 3D lymphoid organoid systems were adopted to examine the function of Tfh cells in B cell helping activity mimicking the GC response. We also used the OVA-immunization and collagen-induced arthritis mouse models in combination with small molecule NIK inhibition to establish a potential role of NIK in Tfh and plasma cell development during autoimmune disease progression.

Results: Stimulation by agonistic anti-CD27 antibodies promoted p52 processing from p100 in human primary T cells, indicating that CD27 activation results in NIK-dependent non-canonical NF-κB signaling. Interestingly, CD27-mediated NIK activation was able to induce IL-21-producing CXCR5⁺ ICOS⁺ PD-1⁺ CD40L⁺ Tfh cell differentiation, whereas it did not affect other T cell differentiation such as Th17 or Treg cells in vitro. Tfh cell development induced by CD27-NIK signaling was partially blocked by the small molecule NIK inhibitor, SMI1. Moreover, SMI1-treated Tfh cells were less potent in the induction of IgD^– CD38^hi CD27^hi plasma cell differentiation and IgG production in both B-T co-cultures and GC organoids. This implies that the inhibition of NIK affects both T and B cells thereby achieving a huge potency in the suppression of inflammation. This was corroborated in the T cell-dependent immunization where administration of SMI1 reduced GC B cell responses and antigen specific antibody production, and ameliorated the progression of disease in collagen-induced arthritis models.

Conclusion: Our findings indicate that NIK-mediated signaling events play an intrinsic role in both Tfh and B cells to regulate immune responses. Targeting NIK may therefore have potential in the treatment of autoimmune diseases.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/nf-%ce%bab-inducing-kinase-is-a-therapeutic-target-for-autoimmune-diseases-by-orchestrating-both-b-cell-and-t-follicular-helper-cell-responses/