Active tuberculosis in the pre-antibiotic era had a grim prognosis, but around 50% of people who developed pulmonary disease were able to recover (albeit typically after a prolonged convalescence). In a newly published study from the UK, researchers identify 27 individuals aged 66-91 years old who survived pulmonary TB prior to the availability of treatment, in order to evaluate their TB-specific memory T cell responses. The median age at the time of active TB disease was 16.5 years, and since that time they have had minimal risk of re-exposure to the mycobacterium. Offering a glimpse into the history of TB control, 17 participants had been admitted to sanatoria while ill.
ELISPOT assays were used to measure interferon gamma or IL-2 production by T cells in response to stimulation with the TB antigens ESAT‐6 and CFP‐10. Responses were detected in 16 (60%) and 19 (70%) of the participants based on interferon gamma and IL-2 production, respectively. More detailed analysis in a subset of participants revealed that most of these responses consisted of memory CD4 T cells making both cytokines simultaneously, a type of response described as “effector memory” or TEM for short. Based on these data, the researchers state: “the presence of circulating T cells that secrete IFN‐γ and IL‐2 ex vivo…indicates that a TEM cell response to M. tuberculosis–specific secreted antigens can persist for up to 58 years after self‐containment of active tuberculosis.” Because TEM cells are thought to be maintained by intermittent re-exposure to antigen, and because ESAT‐6 and CFP‐10 are actively secreted TB antigens, the authors also note that their data “suggests that the cytokine profile we observed in these untreated patients reflects in vivo persistence of viable bacilli.” Therefore it appears that TB has been actively contained by the immune response in these individuals.
Seven study participants did not display interferon gamma-producing TEM cells but nevertheless showed evidence of TB-specific “central memory” (TCM) CD4 T cells. Because TCM cells can persist long-term in the absence of antigen, the researchers suggest that these individuals may have fully cleared TB infection.
The Journal of Infectious Diseases 2010;202:000–000
Kerry A. Millington,1 Sarah Gooding,2 Timothy S. C. Hinks,3 D. John M. Reynolds,2 and Ajit Lalvani1
1Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, 2Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Oxford, and 3Division of Infection, Inflammation and Immunity, Allergy and Inflammation Research, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom
Individuals with self‐healed tuberculosis from the preantibiotic era offer a unique insight into the natural history of and protective immunity to tuberculosis. In 27 such persons whose tuberculosis self‐healed >50 years earlier, circulating Mycobacterium tuberculosis antigen–specific interferon γ (IFN‐γ)– and interleukin 2 (IL‐2)–secreting T cells were detected ex vivo in 16 and 19 individuals, respectively. The M. tuberculosis–specific T cell cytokine profile was dominated by effector memory T cells that secrete both IFN‐γ and IL‐2 and included T cells that secrete only IFN‐γ or IL‐2, suggesting persistence of antigen secreted by viable bacilli. Of 10 individuals with no M. tuberculosis antigen–specific IFN‐γ–secreting T cells detectable ex vivo, 7 had evidence of central memory T cells, consistent with clearance of infection.