ABSTRACT A fundamental question in immunology lies in understanding how the immune system can mount robust T cell responses to foreign pathogens, while restricting collateral damage to endogenous tissues, a state often referred to as self vs. non-self discrimination. Although many self-reactive conventional T (Tconv) cells are removed from the body by clonal deletion, considerable evidence demonstrates that this process is imperfect. The control of remaining self-reactive Tconv cells requires suppression by CD4+Foxp3+ regulatory T (Treg) cells, which function throughout life to prevent autoimmunity. Efforts to define the mechanisms by which Treg cells suppress Tconv cells have revealed numerous potential mechanisms, including the masking of co- stimulatory ligands, the local production of suppressive cytokines, or the hoarding of key accessory factors. However, these antigen non-specific bystander mechanisms are not sufficient to explain self vs. non-self discrimination, especially in the context of innate immune activation during infection, highlighting the importance of new research examining the mechanisms of Treg-mediated suppression. Previously, we identified two self-peptides (C4 and F1 peptides) that are recognized by naturally occurring Treg cell populations and are derived from a single prostate-specific protein, Tcaf3. Here, we demonstrate that selection on the C4 peptide during repertoire formation is critical for the prevention of prostatitis, and that polyclonal Treg cells of other specificities can not compensate for the shift in the C4-specific T cell pool. This reveals a key role for Treg-mediated suppression of Tconv cells of matched peptide/MHC-II (pMHC-II) specificity, as opposed to broad antigen non-specific mechanisms. The objectives of this application are to elucidate mechanisms by which Treg cells coordinate pMHC-II-specific immune suppression at steady state and during infection. We will achieve our objectives in close collaboration with Dr. Ron Germain, an expert in advanced imaging techniques, and Dr. Nancy Freitag, an expert in the genetics of the bacterium Listeria monocytogenes (Lm). In Aim 1, we will use functional experiments and advanced confocal imaging to define the mechanistic basis of pMHC-II- specific Treg cell suppression at steady state, testing the hypothesis Treg cells do not prevent the initial activation of pMHC-II-matched Tconv cells, but instead rheostatically respond to activated Tconv cells to restrict their subsequent differentiation and expansion. In Aim 2, we will define the role of Treg cell pMHC-II specificity in coordinating self vs. non-self discrimination during Lm infection, testing the hypothesis that robust pMHC-II-specific suppression by self-selected Treg cells is imparted by both quantitative (numerical) advantages and qualitative properties induced by the recognition of peripheral self-ligand prior to infection. In all, our work is expected to elucidate key mechanisms by which the immune system orchestrates host defense while limiting collateral damage to self tissues.

U01AI154560

2021-05-01

2026-04-30