title: The absence of cutaneous lymph nodes results in a Th2 response and increased susceptibility to Leishmania major infection in mice.
abstract: Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-beta. The complete absence of LNs due to a genetic depletion of the lymphotoxin-beta receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.
authors.affiliation: Department of Dermatology, Institute of Immunology, Münster University Hospital, 48149 Münster, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ehrchen
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Kirsten
authors.initials: K
authors.lastname: Roebrock
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Wolfram
authors.initials: W
authors.lastname: Domschke
authors.forename: Rodney
authors.initials: R
authors.lastname: Newberry
authors.forename: Clemens
authors.initials: C
authors.lastname: Sorg
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
authors.forename: Torsten
authors.initials: T
authors.lastname: Kucharzik
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Spahn
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D005528:Foot / Q000469:parasitology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008198:Lymph Nodes / Q000002:abnormalities / Q000276:immunology*; D053259:Lymphotoxin beta Receptor / Q000172:deficiency; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors; D053308:Lymphotoxin-beta / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D012867:Skin / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; C505887:Ltb protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D015847:Interleukin-4; D007371:Interferon-gamma