The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.
310 - 323.e7
Animals, B-Lymphocytes, Cell Proliferation, Germinal Center, Immunological Synapses, Lymphocyte Activation, Mice, Mice, Knockout, Mice, Transgenic, Paracrine Communication, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, Receptors, Immunologic, Receptors, Tumor Necrosis Factor, Member 14, Signal Transduction, T-Lymphocytes, Helper-Inducer