Signaling via LTβR & HVEM‐BTLA Pathways Control Dendritic Cell Homeostasis In Vivo

Abstract

Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the Lymphotoxin (LT)‐β receptor, however the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTβR and the ligands, LTα or LTβ, but not LIGHT as well as in NF‐κB inducing kinase (NIK) show a specific loss of CD8α‐ DC subsets. In contrast, the CD8α‐ DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM and BTLA DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA was required in DC and in the surrounding microenvironment, although DC expression of LTβR was necessary to maintain homeostasis. Moreover, enforced activation of LTβR with an agonist antibody drove expansion of CD8α‐ DC subsets overriding the HVEM‐BTLA checkpoint. These results indicate the HVEM‐BTLA pathway provides an inhibitory checkpoint regulating DC homeostasis in lymphoid tissue. Together, the LTβR and HVEM‐BTLA pathways form an integrated signaling network regulating DC homeostasis.