T/B‐cell interactions are more transient in response to weak stimuli in SLE‐prone mice

Abstract

Changes in immune function during the course of systemic lupus erythematosus (SLE) are well characterized. Class-switched antinuclear antibodies are the hallmark of SLE, and T/B- cell interactions are thus critical. However, changes in immune function contributing to disease susceptibility are unknown. Here, we have analyzed primary T and B cells from a mouse model of SLE prior to the onset of disease. To allow cognate T-cell activation with low affinity, we have developed a lower potency peptide ligand for the OTII T-cell receptor. T and B-cell couples formed less frequently and retained their polarity less efficiently preferentially in response to low affinity stimulation in SLE-prone mice. This matched decreased recruitment of actin and Vav1 and an enhanced PKCΘ recruitment to the cellular interface in T cells. The induction of the germinal center B-cell marker GL7 was increased in T/B cell couples from SLE-prone mice when the T-cell numbers were limited. However, the overall gene expression changes were marginal. Taken together, the enhanced cell couple transience may allow a more efficient sampling of a large number of T/B cell couples, preferentially in response to limiting stimuli, therefore enhancing the immune reactivity in the development of SLE.

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

“…Recently, Sinai et al also have reported altered B and T cell interactions to be responsible for increased GC B cell phenotype in vitro in autoimmune prone B6. Sle1 mice (31). …”

B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments

“…SLE patients show aberrant and increased expression of recombination-activating genes (RAG) in peripheral B cells, which can lead to mutation of BCR and thus development of autoreactive B lymphocytes [26]. Aberrant T cell-B cell interaction (e.g., shorted interaction time in the germinal center) results in inadequate anergic signals to autoreactive B cells and hence enhancing their survival [27,28]. Increased BCR-mediated signaling can also lower the activation threshold of peripheral B lymphocytes and promote cellular phenotypes characteristic of SLE [29].…”

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

“…This is despite their having normal central tolerance processes in the bone marrow . In the Sle1 murine model, disease risk is inherited via a region on chromosome 1, carrying polymorphisms in genes encoding multiple receptors needed for T cell–B cell interactions (including Slam , Ly108 , Cd84 , Cracc , and Ly9 ) . In the germinal centers (GCs) of these mice, transient short‐term contact between B cells and T cells allows rare autoreactive B cells and T cells to “sample” many different cells in the GC, increasing chances of interaction for positive costimulation .…”

“…In the Sle1 murine model, disease risk is inherited via a region on chromosome 1, carrying polymorphisms in genes encoding multiple receptors needed for T cell–B cell interactions (including Slam , Ly108 , Cd84 , Cracc , and Ly9 ) . In the germinal centers (GCs) of these mice, transient short‐term contact between B cells and T cells allows rare autoreactive B cells and T cells to “sample” many different cells in the GC, increasing chances of interaction for positive costimulation . Shorter contact times between immune cells are also known to alter their function (e.g., poorer Treg cell ability to induce tolerance in target cells due to shorter contact times) .…”