The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis.

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.