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The protective efficacy of BCG against TB varies with no apparent protection in some population, and mechanisms of its immune protection is poorly known, and yet BCG is the most widely used vaccine, with more than 4 billion BCG-vaccinated children globally. BCG is probably the only licensed vaccine currently in use believed to mediate immune protection through the production of interferon (IFN)-\u03b3 by CD4 T cells, which in turn activates macrophages to kill Mycobacterium tuberculosis (Mtb). Currently, a number of new TB candidate vaccines are in different phases of clinical trial. The majority of these new vaccines are either recombinant forms of BCG or prime boosters of BCG (rBCG) and their immunogenicity is tested using BCG as a benchmark by measuring specific IFN-\u03b3 produced by CD4+ T cells as a protective immune marker. However, some recent studies that examined mechanisms of immune protection of BCG in animals and humans have reported a lack of correlation between IFN-\u03b3 production by CD4 cells and BCG-induced immune protection. These studies point to the fact that there is a missing link in our understanding of TB immunology. Conversely, there is emerging evidence that other T cell subsets (gammadelta, \u03b3\u03b4), CD8+ T cells and natural killer (NK) cells may play a vital role in immune protection against Mtb infection and BCG-induced immune protection. \u03b3\u03b4 T cells and NK cells, which were considered to be part of the innate immunity in the past, have been shown to develop immunological memory upon re-encounter with the same pathogen. In this paper, the controversy over the role of IFN-\u03b3 as a marker for protective immunity against TB, and emerging data on the role of \u03b3\u03b4 T cells, CD8+ and NK cells in TB immunology, will be presented.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2012.04614.x","type":"journal-article","created":{"date-parts":[[2012,5,31]],"date-time":"2012-05-31T11:48:18Z","timestamp":1338464898000},"page":"213-219","source":"Crossref","is-referenced-by-count":85,"title":["Is interferon-gamma the right marker for bacille Calmette\u2013Gu\u00e9rin-induced immune protection? The missing link in our understanding of tuberculosis immunology"],"prefix":"10.1093","volume":"169","author":[{"given":"F","family":"Abebe","sequence":"first","affiliation":[{"name":"Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,8,2]]},"reference":[{"key":"2021122708375993000_b1","volume-title":"Global tuberculosis control: epidemiology, strategy, financing","author":"World Health Organization (WHO)","year":"2009"},{"key":"2021122708375993000_b2","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1016\/S0140-6736(10)60409-6","article-title":"The HIV-associated tuberculosis epidemic \u2013 when will we act?","volume":"375","author":"Haries","year":"2010","journal-title":"Lancet"},{"key":"2021122708375993000_b3","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1016\/S0140-6736(09)60331-7","article-title":"Epidemiology of antituberculosis drug resistance 2002\u201307: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance","volume":"30","author":"Wright","year":"2009","journal-title":"Lancet"},{"key":"2021122708375993000_b4","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.immuni.2010.09.015","article-title":"Future vaccine strategies against tuberculosis: thinking outside the box","volume":"33","author":"Kaufmann","year":"2011","journal-title":"Immunity"},{"key":"2021122708375993000_b5","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/S0140-6736(06)68507-3","article-title":"BCG vaccination on childhood tuberculosis meningitis and miliary tuberculosis world-wide: a meta-analysis and assessment of cost-effectiveness","volume":"367","author":"Trunz","year":"2006","journal-title":"Lancet"},{"key":"2021122708375993000_b6","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/S0140-6736(95)92348-9","article-title":"Variation in protection by BCG: implications of and for heterologous immunity","volume":"346","author":"Fine","year":"1995","journal-title":"Lancet"},{"key":"2021122708375993000_b7","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1001\/jama.1994.03510330076038","article-title":"1994. 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