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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.

Original publication




Journal article



Publication Date





310 - 323.e7


Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.


Germinal Center, B-Lymphocytes, T-Lymphocytes, Helper-Inducer, Animals, Mice, Transgenic, Mice, Knockout, Mice, Receptors, Immunologic, Receptors, Antigen, T-Cell, Proto-Oncogene Proteins c-bcl-2, Lymphocyte Activation, Paracrine Communication, Signal Transduction, Cell Proliferation, Receptors, Tumor Necrosis Factor, Member 14, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Immunological Synapses