Review Article | Published:

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Nature Reviews Immunology (2018) | Download Citation


Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals ‘resisters’. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.

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This work was supported by grants from the US National Institutes of Health grants R01AI124348 (to W.H.B., T.R.H., C.S., C.M.S. and H.M.-K.), U01AI115642 (to W.H.B., T.R.H., C.S., C.M.S. and H.M.-K.), R01AI124349 (to E.S.) and T32AI007044 (to J.D.S.) and contract number NO1AI70022 (to W.H.B., C.M.S., T.R.H. and H.M.-K.); the Bill and Melinda Gates Foundation grant OPP1151836 (to T.R.H., W.H.B., C.S., C.M.S., H.M.-K., G.C. and R.S.W.) and grant OPP1151840 (to G.A. and S.F.); the Canadian Institutes of Health Research grant FDN143332 (to E.S.); and the South African Medical Research Council grant ACT4TB/HIV (to G.C. and R.S.W.). G.C. is also affiliated with the School of Public Health, University of Witwatersrand, Johannesburg, South Africa, and the Advancing Care and Treatment for TB/HIV, South African Medical Research Council, Johannesburg, South Africa. E.S. is also affiliated with the McGill International TB Centre, McGill University, Montreal, Quebec, Canada.

Author information


  1. Department of Medicine, University of Washington, Seattle, WA, USA

    • Jason D. Simmons
    • , Chetan Seshadri
    • , Monica Campo
    •  & Thomas R. Hawn
  2. Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    • Catherine M. Stein
  3. Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

    • Catherine M. Stein
    • , Robert S. Wallis
    •  & W. Henry Boom
  4. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

    • Galit Alter
  5. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA

    • Sarah Fortune
  6. Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada

    • Erwin Schurr
  7. The Aurum Institute, Parktown, South Africa

    • Robert S. Wallis
    •  & Gavin Churchyard
  8. Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda

    • Harriet Mayanja-Kizza


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J.D.S., C.S. and T.R.H. contributed to the drafting and editing of all sections. Focused contributions were made to the Epidemiology and Genetics sections (C.M.S., E.S. and G.C.), the B cell-mediated resistance section (G.A.) and the Macrophage-mediated resistance section (M.C.). Initial figure drafts were provided by J.D.S., M.C. and G.A. Detailed review and editing were additionally provided by S.F., R.S.W., W.H.B. and H.M.-K.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jason D. Simmons.


Purified protein derivative (PPD) skin reactivity test

A delayed-type hypersensitivity test that measures induration at the site of an intradermal injection of peptide extract from mycobacterial culture filtrate. A positive result reflects a pre-specified minimal diameter of skin induration and suggests the presence of latent Mycobacterium tuberculosis infection but may also result from non-M. tuberculosis sensitization, including prior vaccination with Mycobacterium bovis Bacillus Calmette–Guérin. Also known as the Mantoux tuberculin skin test (TST).

Bacillus Calmette–Guérin

(BCG). A culture-adapted, attenuated Mycobacterium bovis strain that is used for vaccination against Mycobacterium tuberculosis.

IFNγ release assays

(IGRAs). Whole-blood immune assays in which a patient’s blood is cultured in the presence of select antigens specific to Mycobacterium tuberculosis and the secretion of IFNγ is quantified. Positive results are independent of prior Bacillus Calmette–Guérin vaccination and negative results ensure a sufficient response to a mitogen positive control.


An individual who remains negative for the purified protein derivative skin reactivity test and the IFNγ release assay throughout serial testing despite heavy exposure to Mycobacterium tuberculosis.

Innate resisters

Conceptually, resisters who immediately clear Mycobacterium tuberculosis following exposure to the bacterium and before priming of any adaptive immune responses.

Adaptive resisters

Conceptually, resisters who clear or contain Mycobacterium tuberculosis infection via T cell and B cell mechanisms but who remain negative for the purified protein derivative skin reactivity test and the IFNγ release assay.

Household contact

An individual who resides within the same domicile as an index case (patient with tuberculosis) for a pre-specified amount of time.

Hyperendemic conditions

Regions in which ongoing Mycobacterium tuberculosis transmission is unusually high owing to an elevated prevalence of tuberculosis.


An occupational pulmonary disease that is prevalent among gold miners owing to protracted inhalation of silicate dust, which leads to scarring and increased Mycobacterium tuberculosis infection.

Relative resistance

A threshold phenomenon in which mechanisms of host resistance to Mycobacterium tuberculosis infection may be overcome owing to frequent or lengthy exposure to contacts with a high bacillary burden.

Ghon complex

The focus of primary Mycobacterium tuberculosis infection in the lung parenchyma that histologically corresponds to a granuloma and radiographically is recognized by its associated lymphadenopathy and calcification.

Quantitative trait locus

(QTL). A genomic region containing polymorphisms that are associated with a quantifiable phenotype, such as the extent of induration (in millimetres) in the purified protein derivative skin reactivity test. When variation at these loci affect the expression levels of specific genes, they are referred to as expression QTLs.

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