title: CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation.
abstract: The costimulatory receptor CD28 and IL-4Ralpha containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Ralpha signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore,immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Ralpha and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Ralpha in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Versbacher Str. 7, Würzburg, Germany. huenig@vim.uni-wuerzburg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Karin
authors.initials: K
authors.lastname: Elflein
authors.forename: Tea
authors.initials: T
authors.lastname: Gogishvili
authors.forename: Monika
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Antony
authors.initials: A
authors.lastname: Cutler
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D004195:Disease Models, Animal; D007109:Immunity; D007249:Inflammation; D015847:Interleukin-4 / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000473:pathology; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014353:Trypanosomiasis, African / Q000276:immunology / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology / Q000473:pathology
chemical_list: D018106:CD28 Antigens; D015847:Interleukin-4
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