title: Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4⁺ T cell responses.
abstract: IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28⁻/⁻ mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28(-/lox)Cre⁺/⁻+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28⁻/⁻ mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28(-/lox)Cre⁺/⁻ mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28⁻/⁻ mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5⁺ T(FH) cell population. Furthermore, total number of CD4⁺ T cells and B220⁺ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28⁻/⁻ mice and tamoxifen treated CD28(-/lox)Cre⁺/⁻ mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4⁺ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28(-/lox)Cre⁺/⁻ mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection.
authors: International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Hlumani
authors: H
authors: Ndlovu
authors: International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Mathew
authors: M
authors: Darby
authors: Institute for Virology and Immunology, University of Würzburg, Würzburg, Germany.
authors: Monika
authors: M
authors: Froelich
authors: International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: William
authors: W
authors: Horsnell
authors: Department of Neuroimmunology, Institute of Multiple Sclerosis Research and The Hertie Foundation, University Medical Center Göttingen, Göttingen, Germany.
authors: Fred
authors: F
authors: Lühder
authors: Institute for Virology and Immunology, University of Würzburg, Würzburg, Germany.
authors: Thomas
authors: T
authors: Hünig
authors: International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Frank
authors: F
authors: Brombacher
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus; D017206:Strongylida Infections / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens