An interaction between the TNFR superfamily member HVEM and BTLA restrains B-cell proliferation in the germinal center.

  • Major finding: An interaction between the TNFR superfamily member HVEM and BTLA restrains B-cell proliferation in the germinal center.

  • Mechanism: Binding of BTLA on Tfh cells to HVEM signals through SHP1 to restrict CD40L in the immunologic synapse.

  • Impact: Restoration of HVEM may be a potential strategy to inhibit lymphomagenesis in the germinal center.


HVEM, a member of the tumor necrosis factor superfamily encoded by the gene TNFRSF14, is the most frequently mutated surface molecule in germinal center (GC)–derived B-cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma. Mintz and colleagues found that HVEM-deficient B cells had higher competitiveness and a proliferative advantage over HVEM–wild-type B cells in the GC. BTLA, a member of the immunoglobulin superfamily and HVEM ligand, is a T-cell inhibitory ligand highly expressed on B and T cells in the GC, mainly on T follicular helper (Tfh) cells. The interaction between HVEM on B cells and BTLA on Tfh cells in the GC immunologic synapse recruited SHP1 in the Tfh cells, inhibited Tfh cell signaling and activation and decreased the mobilization of CD40L to the T-cell surface, resulting in decreased CD40–CD40L interaction in the immunologic synapse. BTLA deficiency led to increased expression levels of BCL2 in B cells and expansion in the GC, indicating that BTLA expressed on Tfh cells serves as a cell-extrinsic suppressor of B-cell expansion in the GC through expression of BCL2. Collectively, these results demonstrate the role of HVEM in the restriction of B-cell expansion through binding to BTLA on Tfh cells. Deficiency in HVEM–BTLA interaction leads to reduced inhibition and increased expansion of B cells in the GC, which might potentially contribute to lymphomagenesis. Evaluation of the therapeutic potential of increasing HVEM levels with chimeric antigen receptor T cells or using soluble HVEM to reduce Tfh function in the setting of HVEM deficiency and inhibit lymphomagenesis may therefore be warranted.

Mintz MA, Felce JH, Chou MY, Mayya V, Shui JW, An J, et al. The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis. Immunity 2019 Jun 13 [Epub ahead of print].

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