The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

Kai Werner, Sebastian Dolff, Yang Dai, Xin Ma, Alexandra Brinkhoff, Johannes Korth, Anja Gaeckler, Hana Rohn, Ming Sun, Jan Willem Cohen Tervaert, Pieter van Paassen, Andreas Kribben, Oliver Witzke, Benjamin Wilde*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3(+)CD4(-)CD8(-). To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3(+)CD4(-)CD8(-)). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.

Original languageEnglish
Article number2843
Number of pages10
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - 10 Dec 2019

Keywords

  • ANCA vasculitis
  • BTLA
  • co-inhibition
  • immune checkpoint
  • Th17 cells
  • T-LYMPHOCYTE ATTENUATOR
  • REGULATORY CD4+T CELLS
  • B-LYMPHOCYTE
  • PERIPHERAL-BLOOD
  • WEGENERS-GRANULOMATOSIS
  • ANTI-BTLA
  • EXPRESSION
  • TOLERANCE
  • ACTIVATION
  • INFILTRATE

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