Role of GLI2 in antibody production

The National Institute of Allergy and Infectious Diseases awarded the University of New Hampshire $1,136,734 on April 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of the transcription factor GLI2 in antibody production and class switch recombination in B cells.

The research combines human monoclonal IgM-secreting B cell lines with conditional transgenic mouse models carrying GLI2 deficiency in B cells and hematopoietic cells to elucidate GLI2's functional role in B cell biology. The project examines two specific hypotheses: that GLI2 directly regulates immunoglobulin heavy chain transcription and class switch recombination by binding to V-region promoters and V-J intron sequences, and that GLI2 indirectly modulates class switch recombination by negatively regulating AICDA expression to influence B cell differentiation. This work addresses dysregulation of immunoglobulin production, a hallmark of malignant and autoimmune disorders, by clarifying molecular mechanisms that remain poorly understood despite advances in antibody production research.

Performance occurs in Lee, New Hampshire, with the period of performance running through March 31, 2029. The award is classified as a Project Grant, the standard assistance type for investigator-initiated research under NIAID's competitive grant program.

Abstract

The regulation of immunoglobulin heavy chain (IGH) transcription and expression is a critical component of antibody secretion by activated b cells. Despite significant advances in understanding the mechanisms driving antibody production, many of the molecular processes involved remain unclear. Dysregulation of immunoglobulin (IG) production is a hallmark of various malignant and autoimmune disorders, highlighting the need for a deeper understanding of the transcriptional regulation ofand class switch recombination (CSR) to target these pathways in IG-related pathologies. While studies on human b cells typically rely on polyclonal populations from peripheral blood or tonsil samples, these models present challenges in comprehensively studyingregulation. To overcome this, we are using novel monoclonal IGM-secreting b cell lines to investigate the transcriptional regulation ofand CSR in human cells. In this proposal, we examine a novel role for the transcription factor GLI2 as a critical checkpoint that facilitates CSR in b cells. By combining human monoclonal IGM-secreting b cell lines and conditional transgenic mouse models with GLI2 deficiency in b cells and hematopoietic cells, we aim to understand the functional role of GLI2 in b cell biology. Specifically, we hypothesize that GLI2 directly regulatestranscription and CSR by binding TOV-region promoters and v-j intron sequences (aim 1), and indirectly modulates CSR by negatively regulating aicda expression, thereby influencing b cell differentiation (aim 2).