a | The 'central dogma' of protective immunity to tuberculosis (TB) is that CD4⁺ T cells produce interferon-γ (IFNγ) (T helper 1 (T_H1) cells), which synergizes with tumour necrosis factor (TNF; produced by the T cell or the macrophage), and together these activate macrophage antimicrobial activity that is capable of restricting the growth of Mycobacterium tuberculosis. Two pathways activated by IFNγ that are capable of killing M. tuberculosis are nitric oxide production and phagosome–lysosome fusion, which acidifies the bacterial phagosome. b | 'A revised view of T cell-mediated immunity' incorporates additional T cell subsets (CD4⁺ T cells, CD8⁺ T cells and unconventional T cells: γδ T cells, mucosal-associated invariant T (MAIT) cells and CD1-restricted T cells) and includes additional mechanisms by which T cells mediate killing of M. tuberculosis. These include additional cytokines (for example, granulocyte–macrophage colony-stimulating factor (GM-CSF)) and cytolysis of infected macrophages. The cytolytic mechanisms vary and can include cytotoxic granules, which can deliver antimicrobial peptides, such as granulysin, but can also deliver granzymes, which can trigger apoptotic cell death. Cytotoxic T lymphocyte (CTL) activity mediated by FAS ligand (FASL)–FAS or TNF can also lead to apoptosis. Apoptosis can have a beneficial effect on the outcome of infection, as infected apoptotic cells can be engulfed by bystander macrophages, which are capable of destroying the apoptotic cells, including any intracellular bacteria. Finally, several components of the innate response, including interleukin-1 (IL-1) and vitamins, can synergize with cytokines that are produced by T cells. c | 'Protective T cells and vaccination' focuses on the desired features of protective T cell responses. Rational vaccine design should aim to elicit protective T cells by optimizing their action on infected cells in several ways. Vaccine-elicited memory T cells must rapidly expand and generate secondary effector T cells that undergo sustained proliferation following activation. Whereas the functions of primary effector T cells are heterogeneously expressed, vaccination can lead to more homogenous expression of effector functions during the recall response. Such T cells, which are often identified as multifunctional T cells, may have a greater protective potential. Primed effector and memory T cells should efficiently traffic to sites of infection, but the kinetics of the response must be balanced with respect to T cell subsets and limit the potential for T cell exhaustion, excessive inflammatory pathology or an ineffective response that hinders T cell–target contact.