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Immunity. 2019 Aug 20;51(2):310-323.e7. doi: 10.1016/j.immuni.2019.05.022. Epub 2019 Jun 13.

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

Author information

1
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.
2
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
3
Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA, USA.
4
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
5
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
6
Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
7
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. Electronic address: jason.cyster@ucsf.edu.

Abstract

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.

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