Membrane lymphotoxin contributes to antileishmanial immunity by controlling structural integrity of lymphoid organs

Abstract

Lymphotoxin (LT)α in combination with LTβ 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 LTβ-deficient mouse strain on a pure genetic C57BL/6 background (B6.LTβ-/-) and compared it to a unique series of LTα-, TNF- and TNF/LTα-gene-targeted mice on an identical genetic background (B6.LTα-/-, B6.TNF-/- and B6 TNF/LTα-/-). B6.LTβ-/- mice lacked peripheral LN with the exception of mesenteric LN, and displayed a disturbed micro-architecture of the spleen, although less profoundly than LTα- or TNF/LTα-deficient mice. Radiation bone marrow chimeras (B6.WT→B6.LTβ-/-) developed Peyer's patch (PP)-like lymphoid aggregates in the intestinal wall indicating a possible role for soluble LTα3 in the formation of the PP anlage. After infection with Leishmania major, B6.LTβ-/- 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-γ and IL-12 were comparable in B6.WT and B6.LTβ-/- mice. Infection of radiation bone marrow chimeras showed that it is the LTβ-dependent presence of lymphoid tissue and not the expression of mLT itself that renders mice resistant to leishmaniasis.