title: Immunization with apoptotic phagocytes containing Histoplasma capsulatum activates functional CD8(+) T cells to protect against histoplasmosis.
abstract: We have previously revealed the protective role of CD8(+) T cells in host defense against Histoplasma capsulatum in animals with CD4(+) T cell deficiency and demonstrated that sensitized CD8(+) T cells are restimulated in vitro by dendritic cells that have ingested apoptotic macrophage-associated Histoplasma antigen. Here we show that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently activated functional CD8(+) T cells whose contribution was equal to that of CD4(+) T cells in protection against Histoplasma challenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8(+) T cell but not the CD4(+) T cell response to pulmonary Histoplasma infection. In mice subcutaneously immunized with viable Histoplasma yeasts whose CD8(+) T cells are protective against Histoplasma challenge, there was heavy granulocyte and macrophage infiltration and the infiltrating cells became apoptotic. In mice subcutaneously immunized with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled apoptotic macrophages containing heat-killed Histoplasma, the CFSE-labeled macrophage material was found to localize within dendritic cells in the draining lymph node. Moreover, depleting dendritic cells in immunized CD11c-DTR mice significantly reduced CD8(+) T cell activation. Taken together, our results revealed that phagocyte apoptosis in the Histoplasma-infected host is associated with CD8(+) T cell activation and that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently evokes a protective CD8(+) T cell response. These results suggest that employing apoptotic phagocytes as antigen donor cells is a viable approach for the development of efficacious vaccines to elicit strong CD8(+) T cell as well as CD4(+) T cell responses to Histoplasma infection.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, No. 1, Ren-Ai Road, Section 1, Taipei, Taiwan.
authors.forename: Shih-Hung
authors.initials: SH
authors.lastname: Hsieh
authors.forename: Jr-Shiuan
authors.initials: JS
authors.lastname: Lin
authors.forename: Juin-Hua
authors.initials: JH
authors.lastname: Huang
authors.forename: Shang-Yang
authors.initials: SY
authors.lastname: Wu
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Chu
authors.forename: John T
authors.initials: JT
authors.lastname: Kung
authors.forename: Betty A
authors.initials: BA
authors.lastname: Wu-Hsieh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005657:Fungal Vaccines / Q000276:immunology*; D005786:Gene Expression Regulation / Q000502:physiology; D006658:Histoplasma / Q000276:immunology*; D006660:Histoplasmosis / Q000276:immunology* / Q000517:prevention & control; D007114:Immunization; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; D005657:Fungal Vaccines; D001613:beta 2-Microglobulin; D052247:Nitric Oxide Synthase Type II