title: T helper subset differentiation in the absence of invariant chain.
abstract: The outcome of murine infection with Leishmania major is regulated by major histocompatibility complex class II-restricted T helper cells. Invariant chain-deficient (Ii -/-) mice have impaired ability to present major histocompatibility complex class II-restricted antigens, and reduced numbers of CD4+ T cells. Despite these deficits, C57BL/6 Ii -/- mice controlled L. major infection comparably to wild-type mice. As assessed by mRNA analysis and in vitro antigen restimulation for IFN-gamma, Ii -/- mice had normal induction of Th1 subset differentiation even though antigen-dependent proliferation of their lymph node cells was substantially compromised. In addition, BALB/c Ii -/- mice exhibited a progressive course of infection and Th2 effector cell development that were comparable to that seen in wild-type BALB/c mice. We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro. In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN-gamma-or IL-4-secreting T helper cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic. These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation signals may facilitate the full differentiation of T helper subsets during limiting presentation of antigenic peptides.
authors.affiliation: Department of Medicine, Gwen Knapp Center for Lupus & Immunology Research, University of Chicago, Illinois 60637, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Brown
authors.forename: K
authors.initials: K
authors.lastname: Swier
authors.forename: N H
authors.initials: NH
authors.lastname: Moskowitz
authors.forename: M F
authors.initials: MF
authors.lastname: Naujokas
authors.forename: R M
authors.initials: RM
authors.lastname: Locksley
authors.forename: S L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis*; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D007127:Immunoglobulin Constant Regions; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma