CD4+ T cell receptor sequences during progression towards experimental pemphigoid

Abstract

Autoantibody-mediated diseases, such as epidermolysis bullosa acquisita (EBA), arise from a breakdown in immune tolerance, often reflected in restricted T-cell receptor repertoires (TCRRs). This thesis examines two complementary strategies for restoring tolerance, both of which converge on reshaping the TCRR. In the EBA model, pretreatment with ovalbumin in combination with Alum and TiterMax (OAT) has been shown to completely prevent disease. Building on this model, herein, we demonstrate that OAT pretreatment significantly reshaped the T follicular helper repertoire. OAT increased diversity, reduced clonal dominance, and introduced novel sequence features. Transcriptomic analysis revealed node-specific programs, with the inguinal lymph node (Ingln) shifting toward regulatory and metabolic pathways, consistent with a tolerogenic environment. A second strategy examined the effects of cell-derived nanoparticles (CDNPs), which are multi-epitopic protein aggregates of ~150 nm, reproducibly marked by Annexin A5. CDNPs modestly reduced IL-6 secretion from macrophages and broadened TCRβ repertoires within splenic T-cell zones by limiting clonal dominance. CDNPs also increased Tcrb and Gata3 expression, indicating enhanced T-cell activity with a Th2-associated bias. Together, these findings highlight two distinct but complementary approaches: OAT illustrates how antigen-specific immune deviation can reshape repertoires and support tolerance, whereas CDNPs act as multi-epitope modulators capable of reprogramming both innate and adaptive immunity. From a translational perspective, OAT suggests a model for tolerogenic vaccination in diseases with known antigens, while CDNPs provide a potential therapy where autoantigens are diverse or undefined. Both approaches underscore the TCRR as a central determinant of tolerance and a promising therapeutic target in autoantibody-driven disease.