title: Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM) cells which expand following virulent mycobacterial challenge.
abstract: To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM)) cells in vaccinated mice. These CD4+CD44(hi)CD62L(lo)CD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months) in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM) cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM) cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM) in the lung may represent a new generation of TB vaccines.
authors: TB Research Group, Animal Health and Veterinary Laboratories Agency (AHVLA), Addlestone, Surrey, United Kingdom.
authors: Daryan A
authors: DA
authors: Kaveh
authors: Véronique S
authors: VS
authors: Bachy
authors: R Glyn
authors: RG
authors: Hewinson
authors: Philip J
authors: PJ
authors: Hogarth
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D009163:Mycobacterium bovis / Q000276:immunology / Q000472:pathogenicity*; D010641:Phenotype; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014774:Virulence / Q000276:immunology
chemical_list: D015703:Antigens, CD; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma