Coreceptor therapy-induced de-differentiation of autoreactive Tfh

SUMMARY/ABSTRACT Type 1 diabetes (T1D) is characterized by the T cell-mediated destruction of the insulin producing b cells in the islets of Langerhans. Currently, there is no cure for T1D, highlighting the ongoing need for immunotherapies that effectively suppress b cell autoimmunity long-term for disease prevention and treatment. Recently, T follicular helper cells (Tfh) have been implicated in promoting the diabetogenic response. Notably, persistently high levels of Tfh correlate with nonresponsiveness to CTLA4-Ig therapy in T1D patients. This observation suggests that it is necessary to tolerize Tfh to effectively suppress T1D. With this in mind, we propose to exploit the inherent plasticity of Tfh to limit their fitness and function, while promoting Tfh conversion into functional regulatory T cells (Treg). To achieve this, we will evaluate the efficacy of coreceptor therapy (CoRT), using low-dose nondepleting (ND) Ab specific for CD4 to induce Tfh de-differentiation and conversion into Treg. Our prior work has demonstrated that high-dose CoRT has potent in vivo effects on the properties of murine and human effector T cells (Teff), restoring b cell tolerance in NOD mice, and blocking pathogenic Teff activity in humanized mice. This R21 proposal outlines two Specific Aims. In the first Aim, we will assess the efficacy of low-dose CoRT to promote de-differentiation of murine and human Tfh and subsequent conversion into Treg, as well as investigate mechanisms that regulate this process. In the second Aim we will define the pathogenic versus suppressor function of CoRT-induced, de-differentiated murine and human Tfh. Through this work, we aim to establish a novel approach to both selectively block the pathogenic activity of autoreactive Tfh, while enhancing protective immunoregulation. In addition to T1D, this approach will be applicable to other autoimmune diseases and pathologies where Tfh play a role. Project Number: 1R21AI197041-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Roland Tisch | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $427,625 | Activity Code: R21 | Study Section: Mechanisms of Autoimmunity Study Section[MAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19704101