The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin 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)-beta receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTalpha, LTbeta, LTbetaR, and the NFkappaB inducing kinase show a specific loss of CD8- DC subsets. In contrast, the CD8alpha- 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 LTbetaR was necessary to maintain homeostasis. Moreover, enforced activation of the LTbetaR with an agonist Ab drove expansion of CD8alpha- 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 LTbetaR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.
De Trez
Carl
C
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Schneider
Kirsten
K
Potter
Karen
K
Droin
Nathalie
N
Fulton
James
J
Norris
Paula S
PS
Ha
Suk-won
SW
Fu
Yang-Xin
YX
Murphy
Theresa
T
Murphy
Kenneth M
KM
Pfeffer
Klaus
K
Benedict
Chris A
CA
Ware
Carl F
CF
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D006706:Homeostasis; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000378:metabolism*
C488868:BTLA protein, mouse; D016827:CD8 Antigens; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14