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The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis

  • Author(s): Mintz, Michelle Amy
  • Advisor(s): Cyster, Jason G
  • et al.
Abstract

TNF receptor family member HVEM is one of the most frequently mutated surface proteins in germinal center (GC) derived B cell lymphomas, yet the role of HVEM in normal GCs is unknown. We found that HVEM-deficiency intrinsically increased B cell competitiveness during pre-GC and GC responses. The Ig superfamily molecule BTLA was identified as the ligand regulating these responses, and B cell-intrinsic signaling via HVEM and BTLA was not required. Instead, BTLA signaling into the T cell through SHP1 reduced TCR signaling and the amount of preformed CD40L mobilized to the immunological synapse and thus diminished the help delivered to B cells. Moreover, T cell-deficiency in BTLA cooperated with B cell Bcl-2-overexpression in leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells in a manner that influences GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.

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