Genetics-based discovery of novel genes regulating follicular helper T cell function

About This Grant

ABSTRACT The goal of the studies in this proposal is to establish how disease-associated genetic variation regulates antibody responses at the level of B cell help by follicular helper T cells (TFH). In Aim 1, we will use a powerful combination of state-of-the-art, variant-to-gene mapping approaches in follicular T cells ‘caught in the act’ of helping B cell antibody responses in human lymphoid tissue: 1) chromosome conformation data to reveal physical associations between regulatory variants and gene promoters in the context of the 3D structure of the genome, 2) quantitative expression-trait mapping to reveal statistical associations between disease-associated variants and gene expression in TFH cells, 3) massively-parallel reporter assays to identify expression- modulating variants, and 4) CRISPR interference screens to identify genes regulated by antibody disease variants in TFH cells. In Aim 2, ‘novel’ effector genes prioritized by the approaches in Aim 1 will be assessed for roles in TFH function in an in vitro lymphoid organoid model human humoral immunity and in in vivo mouse models of lupus and influenza vaccination. The proposed studies are supported by the extensive experience and preliminary data of the research team, and will use a confluence of evidence from orthogonal approaches to power discovery of novel mechanisms that regulate T cell-dependent humoral immunity, refine our understanding of how common genetic variation contributes to autoimmune disease susceptibility, and point to novel therapeutic interventions to modulate humoral immunity in the context of vaccines, infectious disease, and autoimmune disorders.