Membrane lymphotoxin contributes to anti-leishmanial immunity by controlling structural integrity of lymphoid organs.
Lymphotoxin (LT)alpha in combination with LTbeta forms membrane-bound heterotrimeric complexes with a crucial function in lymph node (LN) organogenesis and correct morphogenesis of secondary lymphoid tissue. To study the role of membrane LT (mLT) in lymphoid tissue organogenesis we generated an LTbeta-deficient mouse strain on a pure genetic C57BL/6 background (B6.LTbeta-/-) and compared it to a unique series of LTalpha-, TNF- and TNF/LTalpha-gene-targeted mice on an identical genetic background (B6.LTalpha-/-, B6.TNF-/- and B6 TNF/LTalpha-/-). B6.LTbeta-/- mice lacked peripheral LN with the exception of mesenteric LN, and displayed a disturbed micro-architecture of the spleen, although less profoundly than LTalpha- or TNF/LTalpha-deficient mice. Radiation bone marrow chimeras (B6.WT-->B6.LTbeta-/- developed Peyer's patch (PP)-like lymphoid aggregates in the intestinal wall indicating a possible role for soluble LTalpha(3) in the formation of the PP anlage. After infection with Leishmania major, B6.LTbeta-/- mice developed a fatal disseminating leishmaniasis resulting in death after 8 to 14 weeks, despite the natural resistance of the C57BL/6 genetic background (B6.WT) mice to the parasite. Both, the cellular and the humoral anti-L. major immune responses were delayed and ineffective. However, the expression pattern of the key cytokines IFN-gamma and IL-12 were comparable in B6.WT and B6.LTbeta-/- mice. Infection of radiation bone marrow chimeras showed that it is the LTbeta-dependent presence of lymphoid tissue and not the expression of mLT itself that renders mice resistant to leishmaniasis.
Institut für Klinische Mikrobiologie, Immunologie und Hygiene der Universität Erlangen-Nürnberg, Erlangen, Germany.
Patricia
P
Wilhelm
D Sean
DS
Riminton
Uwe
U
Ritter
Frances A
FA
Lemckert
Christina
C
Scheidig
Robert
R
Hoek
Jonathon D
JD
Sedgwick
Heinrich
H
Körner
D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D002462:Cell Membrane; D002678:Chimera; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D007422:Intestines / Q000276:immunology / Q000473:pathology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000913:Antibodies, Protozoan; D016207:Cytokines; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha