B cell-dependent regulatory T cells

Many human autoimmune diseases are associated with the expansion of self-reactive B cells and the elevated production of autoantibodies targeting self-constituents, which can contribute to the initiation, propagation, and exacerbation of disease pathogenesis. Despite the existence of multiple layers of B cell tolerance, including clonal deletion, B cell receptor (BCR) editing, and adoption of dysfunctional states, a measurable fraction of B cells in healthy individuals express self-reactive BCRs and can participate in germinal center reactions, suggesting the need for additional layers of extrinsic control. In this proposal, we examine the hypothesis that a subset of Foxp3-expressing regulatory T (Treg) cells, which are required throughout life for the prevention of autoimmunity and the maintenance of immune homeostasis, are specialized to form direct liaisons with B cells and control the differentiation of self-reactive B cells and the production of autoantibodies. This notion is suggested by an expanding body of compelling indirect evidence, and directly supported by new foundational evidence from our lab. First, we used single cell RNA sequencing to identify two clonally related clusters of Treg cells that are significantly underrepresented in mice lacking MHC-II expression by B cells. This identified unique transcriptional signatures expressed by these B cell dependent Tregs, and identified T cell receptors expressed by these cells. Second, we conducted a TCR profiling screen to define the extent to which the clonal composition of the Treg cell repertoire is dependent on the B cell compartment, and identified numerous B cell dependent Treg cell clones that are lost in mice with restricted B cell diversity. The objectives of this proposal are to identify BCD Tregs at the clonal and polyclonal level, define their developmental requirements and peripheral functions, and identify natural self-peptide ligands recognized by these cells. We will test the central hypothesis that select Treg cell clones differentiate in the thymus following recognition of self-ligands displayed by B cells and are specialized to regulate peripheral self-specific B cells at steady state and during an immune response. In Aim 1, we will define the pathways governing the development and peripheral homeostasis of B cell dependent Treg cell clones. In Aim 2, we will determine the functional role of B cell dependent Treg cells in regulating B cell responses at steady state and following an immune response. In Aim 3, we will identify self-peptide ligands recognized by B cell dependent Treg cells. Overall, our work is expected to define direct bidirectional interactions between Treg cells and the B cell compartment, illuminating a regulatory network that is critical for maintaining B cell tolerance. Project Number: 1R01AI186280-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Peter Savage | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $807,799 | Activity Code: R01 | Study Section: Mechanisms of Autoimmunity Study Section[MAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18628001A1