Expression of lymphotoxin beta governs immunity at two distinct levels.
Interaction of lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTbeta on different lymphocyte subsets to determine how the LTbeta-dependent lymphoid structure influences immune reactivity. All conditionally LTbeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTbeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTbeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTbeta expression influences immune reactivity at two distinct levels: (i) Expression of LTbeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTbeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.
Junt
Tobias
T
Institute of Experimental Immunology, Zürich, Switzerland. junt@cbrinstitute.org
Tumanov
Alexei V
AV
Harris
Nicola
N
Heikenwalder
Mathias
M
Zeller
Nicolas
N
Kuprash
Dmitry V
DV
Aguzzi
Adriano
A
Ludewig
Burkhard
B
Nedospasov
Sergei A
SA
Zinkernagel
Rolf M
RM
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D015870:Gene Expression; D007109:Immunity / Q000276:immunology*; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000002:abnormalities / Q000276:immunology / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018353:Rhabdoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D014771:Virion / Q000276:immunology
C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins