Autoreactive T cells in lupus
openNIAID - National Institute of Allergy and Infectious Diseases
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of adaptive immune
tolerance in conjunction with innate immune system hyperactivity. Autoantibodies, produced by plasma cells
derived from activated B cells, form proinflammatory immune complexes. These immune complexes drive feed
forward loops that sustain a systemic inflammatory environment and deposit in tissues leading to potentially
fatal organ damage. B cells receive help from T cells to produce antibodies. They also contribute to disease by
shaping T cell responses and secreting cytokines. Recent case reports in which SLE patients were treated with
anti-CD19 CAR-T cell therapy to deplete B cells highlight the pathogenic role of B cells in lupus and their value
as a therapeutic target. However, a better understanding of how autoreactive B cells interact with autoreactive
T cells may reveal more targeted points of therapeutic intervention that specifically block autoreactive
responses while sparing protective ones. Antigen specific interactions between CD4+ T cells and B cells are
required for the development of autoimmune disease in lupus. However, whether these critical interactions
occur in germinal centers, where competition for CD4+ T cell help selects high affinity B cells, or in
extrafollicular responses, where B cells may avoid peripheral tolerance checkpoints, is unclear. Gene
expression profiles and pathways specific to autoreactive CD4+ T cells, and how they are shaped by their
interaction with autoreactive B cells, are also ill defined. CD8+ T cells, which recognize antigen presented on
MHC Class I, have also been suggested to modulate the fate of autoreactive B cells. They can directly kill
autoreactive B cells as a means of tolerance, and a subset of CD8+ T cells has recently been shown to have B
cell helper function. Whether and how such interactions between B and CD8+ T cells enhance or suppress the
development of lupus is unknown. Here, we will use genetic and in vivo proximity labeling approaches to
address these knowledge gaps. In Aim 1, we will test the hypothesis that antigen specific interactions between
B and CD8+ T cells promote B cell activation and autoantibody production in lupus. We will prevent B cells,
but not other cells, from undergoing cognate interactions with CD8+ T cells via B cell-specific deletion of B2M,
a component of the MHC Class I complex, in two lupus models. In Aim 2, will use the uLIPSTIC in vivo
proximity system to label all T cells interacting with B cells in lupus models compared to wild type controls.
Features specific to these autoreactive T cells will be defined by flow cytometry, scRNA Seq, and scTCR-Seq.
These studies will provide valuable molecular and cellular insight into the mutual activation of B and T
cells in lupus. They will set the stage for future mechanistic studies defining the role of autoreactive T
cell specific genes and pathways and potentially highlight new therapeutic targets specific to
autoreactive B/T interactions.
Up to $249K
health research