Thursday, January 2, 2025
1/2/2025
SUMMARY. Loss of B cell tolerance and production of auto-antibodies (Ab) by plasma cells (PCs) play a major role in Systemic Lupus Erythematosus (SLE) pathology. Though Ab-dependent pathogenesis can be partially controlled with immunosuppression, there is no cure for Ab-mediated disorders. One of the main limitations when developing therapeutic strategies aimed to prevent Ab-dependent pathology is the lack of a precise understanding of how auto-reactive PCs are generated and maintained. In this regard, T follicular helper (Tfh) cells, a subset of CD4+ T cells that provides help to B cells, play a critical role in promoting auto-reactive PCs. As such, the expansion of self-reactive Tfh cells correlates with auto-Ab production and disease severity in murine and human lupus. Similar to Tfh cells, Double-negative (DN) T cells, a particular population of T cells that characteristically lack CD4 and CD8 expression, are also expanded in lupus. Importantly, the frequency of DN T cells also correlates with disease activity and auto-Ab production. Thus, it is generally believed that these cells play a role in autoimmune disease pathogenesis. Despite their putative role in disease development, we do not know what signals control DN T cell formation, and their exact origin and pathogenic function remain largely elusive. Furthermore, the mechanisms that regulate DN T cell homeostasis are entirely unknown, and there are currently no therapies to selectively deplete DN T cells in vivo. The main goal of this proposal is to define the cellular and molecular mechanisms that control pathogenic DN T cell development and function. In this regard, our preliminary data demonstrate that DN T cells and Tfh cells share phenotypic, transcriptional, and developmental requirements. As such, we have identified a population of Bcl6+ DN T cells that phenotypically resemble Tfh cells. The central hypothesis that will be tested in this proposal is that Tfh cells are the precursors of Bcl6+ DN T cells and that, similar to Tfh cells, these cells are efficient B cell helpers. Importantly, our preliminary data also suggest that Bcl6+ DN T cells are more plastic than Tfh cells, which allows them to acquire a “hybrid” Tfh/Th17 signature that we believe is critical for supporting auto-reactive PC responses. In Aim 1, we will test the hypothesis that Tfh cells are precursors of Bcl6+ DN T cells and examine the capacity of these cells to help self-reactive B cell responses. In Aim 2.1, we will test the hypothesis that IL- 17 production by DN T cells is critical for supporting PC responses and Ab-mediated pathology. In Aim 2.2, we will determine the molecular mechanisms controlling the acquisition of a “hybrid” Tfh/Th17 signature. Finally, in Aim 3, we will develop a new synergistic IL-2-based immunotherapy aimed to selectively target Tfh and prevent the differentiation of IL-17+Bcl6+DN T cells by combining “ultra-low” doses of rIL-2 with STAT3- signaling blockade. We believe that our studies will provide a new paradigm for how pathogenic DN T cells are generated, will reveal new pathways implicated in autoimmune disease pathogenesis, and will be crucial for designing new therapeutic interventions to target Tfh and DN T cells and prevent Ab-mediated pathology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).