Investigating B cell and T cell Cognate Interactions in Systemic Lupus Erythematosus: A Novel System for the Study of Lupus Antigen-Specific T cells

Systemic lupus erythematosus (SLE) is a debilitating disease caused by a misdirected immune response towards self tissues that results from a combination of allelic risk factors, environmental influences, and stochastic events. While the various permutations of these components can be distinct for individual patients, the interactions between autoreactive B cells and T cells are likely to be a common critical force that drives disease pathogenesis.;Previous work has demonstrated that B cells have multiple antibody-dependent and -independent roles in SLE. Studies using B cell deficient lupus-prone mice suggest that B cells may be critical antigen presenting cells (ADCs) for initiating the T cell response, but this has never been directly tested. By specifically deleting MHC class II (MHCII) on B cells, we demonstrated that B cells do play a non-redundant role in activating T cells in a spontaneous, polygenic murine model of lupus. We also show that the ability of B cells to interact with T cells in a cognate manner significantly enhanced B cell proliferation and differentiation into antibody forming cells (AFCs). In the absence of these antigen-specific interactions, clinical disease was significantly reduced.;Understanding the mechanistic detail of these interactions has been significantly hampered by the absence of a lupus antigen-specific T cell model. This is in large part because identifying T cells that recognize ubiquitous self antigens has been extremely challenging. We developed a system to identify immune complex (IC)-specific T cells using rheumatoid factor (RF) B cells and autoantibodies which form spontaneous immune complexes. Since ICs are complex, undefined self antigens, they provided the opportunity to discover previously unknown T cell self antigens. Proteomic techniques and bioinformatic analysis identified several potential self antigens for these T cells, most of which were from ubiquitous nucleic acid-binding proteins.;We used one of these newly characterized autoreactive T cell clones to investigate cognate T cell-B cell interactions in response to lupus autoantigens. We found the IC-specific T cells significantly enhanced the RF B cell response to nucleic acid-reactive autoantibodies. In vitro, the cognate help provided by the IC-specific T cells alleviated the requirement of TLR signaling for the RF B cell proliferative response. In vivo, the presence of IC-specific T cells dramatically altered B cell differentiation, directing anti-chromatin stimulated-B cells from a plasmablast to a germinal center (GC) fate.;The work described here established a new method for identifying autoreactive T cells and discovering new T cell antigen relevant for systemic autoimmune disease.