A novel CD4+ cell subset co-expressing these three Th1 cytokines and IL-17 was induced in adolescents, while a novel CD4+ T-cell subset co-expressing Th1 cytokines and GM-CSF was induced in children. Ag-specific CD8+ T cells were not detected. We conclude that in adolescents and children MVA85A safely induces the type of immunity thought to be important in protection against TB. This includes induction of novel Th1-cell populations that have not been previously described in humans. Vaccines have made a significant impact on morbidity and mortality caused by bacterial and viral infections NVP-BKM120 mouse in humans. Mycobacterium bovis BCG confers consistent
and reliable protection against miliary tuberculosis (TB) and TB meningitis in infants 1, 2. However, BCG has variable – mostly poor – efficacy in protecting against adult and childhood pulmonary disease 3. The immunological mechanisms underlying the observed protection are not understood. Control of Mycobacterium tuberculosis (M.tb) infection and prevention or delay in the onset of TB disease are thought to depend on a T-cell immune response. CD4+ T cells are central
in this response, while selleck screening library it is likely that CD8+ T cells also contribute 4, 5. Th1 cytokines, including IFN-γ 6–8 and TNF-α 9–11, are likely critical in effective immune responses. IL-2 may also be important, as this Th1 cytokine is required for secondary expansion of memory T cells 12 and, thus, for vaccine-induced generation of long-lived immunity. Further, T cells that simultaneously express the three Th1 cytokines IFN-γ, TNF-α and IL-2, referred not to as polyfunctional T cells, have been associated with more effective control of murine intracellular infections 13, including M.tb14. GM-CSF, a cytokine expressed by multiple immune cells including T cells, macrophages and endothelial cells, has been identified as potentially important in anti-mycobacterial immunity. GM-CSF KO mice infected with M.tb show reduced inflammatory and Th1 responses in the lung, leading to local necrosis and rapid death 15. Restoration of expression
of GM-CSF only in the lungs of these KO mice fails to induce normal granuloma formation – these mice also succumb to M.tb. A well-regulated GM-CSF response may therefore be required for effective containment of bacterial growth in the lung 15. M.tb-specific GM-CSF-expressing CD4+ T cells have been detected in children with TB or latent M.tb infection, suggesting a role for this cytokine in anti-mycobacterial immunity 16. Another cytokine, IL-17, may also have a role in protective immunity against TB. In the mouse, IL-17-expressing memory CD4+ T cells (Th17 cells) are induced by vaccination against TB. These cells trigger expression of the chemokines CXCL9, CXCL10 and CXCL11 in the lung, which, in turn, may mediate recruitment of protective Th1 cells to the airways 17.