AUTHOR=Fromm Phillip D. , Kling Jessica C. , Remke Annika , Bogdan Christian , Körner Heinrich TITLE=Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response JOURNAL=Frontiers in Microbiology VOLUME=6 YEAR=2016 URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.01520 DOI=10.3389/fmicb.2015.01520 ISSN=1664-302X ABSTRACT=

Induction of inducible nitric oxide synthase in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. In previous experiments, we observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF^-/- mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient for membrane and soluble TNF (Tnf^-^/^-), for soluble TNF alone (memTnf^Δ/Δ), or the TNF receptors type 1 (Tnfr1^-^/^-) or type 2 (Tnfr2^-^/^-). We detected locally and systemically increased levels of the cytokine IFN-γ in the absence of the TNF-TNFR1-signaling pathway. An analysis of transcription factors and cytokines revealed that activated Tnf^-^/^- CD4⁺ T cells displayed a highly active Th1 phenotype with a strong usage of the T cell receptor Vβ5.1/2. From these data we conclude that the fatal outcome of L. major infection in Tnf^-^/^- mice does not result from a skewed or deficient Th1 differentiation.