In lupus, the body’s immune system mistakenly attacks its own cells and tissues. This attack is driven by the production of autoantibodies, which develop with the help of T follicular helper (Tfh) cells. These Tfh cells interact with B cells, leading to the production of autoantibodies that can cause significant damage. Still, it is not well understood how T cells contribute to the progression of lupus, particularly in tissues. Dr. Moderbacher will use a two-pronged approach to investigate autoreactive T cells. First, she will use a technique called the activation-induced marker (AIM) assay, originally developed to identify infection- and vaccine-induced T cells, to study T cells in great detail and identify T cells contributing to disease in people with lupus. Secondly, she will utilize a pioneering new technique involving nasal swabbing to sample lymphoid tissue located in the upper respiratory tract and identify disease-specific T cells at tissue sites where lupus autoantibodies are produced.

Using the AIM assay, she will detect different types of CD4+ T cells, including Tfh cells, regulatory T (Treg) cells, and CD8+ T cells, and identify those that are self-reactive (targeting the body’s own cells). She will also use advanced techniques to study changes in the genes these autoreactive T cells express, creating a detailed “fingerprint” of problematic cell populations. She will look for changes in the number, proportion, or characteristics of T cells in the blood and upper respiratory tract lymphoid tissue of lupus patients compared to healthy individuals to uncover unprecedented insights into T cell responses in lupus. This project will also explore the feasibility of utilizing minimally invasive nasal swabbing as a means to track disease progression and/or responses to treatment.

What this means for people with lupus

Dr. Moderbacher’s study could greatly enhance the understanding of how T cells contribute to SLE, leading to better ways to track disease progress and develop new treatments. By identifying specific T cell populations that drive the disease, researchers can create more targeted therapies, potentially reducing symptoms and improving the quality of life for lupus patients.

This project aims to address a significant gap in our understanding of the role of autoantigen-specific T cells in systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the production of pathogenic autoantibodies, facilitated by T follicular helper (TFH) cells within germinal centers (GCs) in lymphoid tissues and characterized by immune complex-mediated tissue damage and systemic inflammation driven in part by CD4+ and CD8+ T cells. Despite the obvious importance of T cells to autoantibody production and SLE pathogenesis, there remains a major gap in our understanding of how these cells contribute to disease.

Despite the established role of T cells in SLE pathogenesis, current knowledge is limited due to reliance on population-level analyses and narrow investigations of autoantigen-specific T cells. Our study will leverage the Activation Induced Marker (AIM) assay, a robust technique, which allows for the identification of antigen-specific T cells without requiring prior knowledge of specific T cell epitopes or donor HLA types. The AIM assay employs peptide megapools (MPs) of overlapping peptides to capture a broad array of antigen specificities and T cell receptor (TCR) affinities, enabling comprehensive profiling of CD4+ and CD8+ T cell subsets, including TFH, regulatory T cells (Treg), TH1, and TH17 cells.

We will combine this with nasopharyngeal (NP) swabbing, a minimally invasive technique refined in our lab to sample immune cells from the upper respiratory tract (URT). This approach provides access to epithelial and adenoid tissues, allowing us to identify both resident memory T (TRM) cells and lymph node-associated T cell subsets, including GC TFH cells. Our project involves two specific aims:

1. Identify and characterize autoreactive T cells in peripheral blood in SLE: Using the AIM assay, we will detect and phenotype autoreactive CD4+ and CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from SLE patients. We will perform single-cell RNA and TCR sequencing to generate a detailed “fingerprint” of autoreactive T cell subsets and compare their gene expression profiles to those of T cells specific for exogenous antigens.

2. Investigate autoreactive T cell populations in the URT via NP swabbing in SLE patients: We will examine the composition, activation status, and TCR usage of URT T cell populations in SLE patients relative to healthy controls. The “fingerprints” generated from peripheral blood analyses will be used to identify autoreactive T cells, particularly autoreactive GC TFH cells, in NP samples.

This combinatorial approach is poised to uncover new biological insights into autoreactive T cells across tissues in SLE, identify novel biomarkers for disease monitoring, and suggest new therapeutic targets for limiting disease progression and improving patient outcomes.