The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin β receptor signaling to achieve homeostasis of dendritic cells

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 LTα, LTβ, LTβR, and the NFκB inducing kinase show a specific loss of CD8^- 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-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LTβR was necessary to maintain homeostasis. Moreover, enforced activation of the LTβR with an agonist Ab drove expansion of CD8α^- DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LTβR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.