T Cells and Tuberculosis: Beyond Interferon-γ
- Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Reprints or correspondence: Prof. Ajit Lalvani, Tuberculosis Immunology Group, Dept. of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom (a.lalvani@imperial.ac.uk)
The cytokine interferon-γ (IFN-γ) plays a pivotal role in protective immunity against intracellular pathogens. Specifically, in Mycobacterium tuberculosis (MTB) infection, IFN-γ is an important mediator of macrophage activation [1]. Mice deficient in the gene for IFN-γ are susceptible to fatal tuberculosis (TB) [1, 2], and humans deficient in either the gene for IFN-γ or the IFN-γ receptor show enhanced susceptibility to mycobacterial infections [3]. Measurement of the IFN-γ response to MTB infection has been exploited in research and in clinics, to evaluate and develop new tools for the prevention, diagnosis, and treatment of infection. For example, the development of standardized quantitative ex vivo assays of T cell function, along with the discovery of antigens that are highly specific for MTB, led us [4, 5] and other investigators [6] to develop new diagnostic tools for the detection of MTB infection. These T cell IFN-γ release assays have been and continue to be validated in the field [7], and they are now commercially available in enzyme-linked immunospot (ELISPOT) assay and whole-blood ELISA formats. In clinical trials of new TB vaccines, IFN-γ is used as an indicator of vaccine immunogenicity. However, although IFN-γ is necessary for host immunity against TB, this cytokine alone is not sufficient to provide protection, and more of the cytokine is not necessarily better, because IFN-γ also correlates with extent of immunopathologic findings [8]. However, in the absence of a defined correlate of protective immunity, IFN-γ has hitherto been the most widely used measurement. Given that IFN-γ is simultaneously a marker of infection, immunity, and extent of immunopathologic findings, could moving beyond the use of IFN-γ as a means of reading Th1-type T cell responses yield more clinically and immunologically informative biomarkers of infection and disease?
Our knowledge and understanding of T cell functional diversity in different infections and in different stages (e.g., between the latent and active phases) of an infection remain limited. Moreover, the precise relationship between T cell function and protective immunity is not known for most important infections, including TB and HIV infection. Heterogeneity in memory T lymphocytes, which can be broadly defined as 2 distinct populations of central memory and effector memory cells characterized by a distinct homing capacity and effector function [9]. Effector memory cells display immediate effector function, such as secretion of IFN-γ and interleukin (IL)–2, whereas central memory cells lack immediate effector function and predominantly secrete IL-2 but can efficiently differentiate into effector memory cells on secondary stimulation. Secretion of IFN-γ by different T cell populations challenges our ability to interpret data based only on IFN-γ secretion. For example, ex vivo measurements of IFN-γ production in response to MTB antigens cannot clearly differentiate whether the cytokine is being secreted by effector T cells secreting only IFN-γ or by effector memory cells secreting IFN-γ and IL-2. The immunologic importance and clinical relevance of measuring T cell functions—other than just IFN-γ production—in response to intracellular infections have recently come to light
The emerging picture is that distinct IFN-γ/IL-2 functional profiles correlate with different models of infection: (1) CD4 T cells secreting only IFN-γ predominate in infections with an acute or persistently high antigen load—for example, acute untreated HIV-1 infection, chronic progressive HCV infection, and untreated TB [10–13]; (2) a polyfunctional response of CD4 T cells secreting IFN-γ only, IFN-γ/IL-2, or IL-2 only is characteristic of infections with a persistently low antigen load (e.g., latent asymptomatic cytomegalovirus infection) [11]; and (3) CD4 T cells secreting only IL-2 are associated with cleared or treated infections [11, 13–15]. The lack of IL-2 secretion in infections with an acutely or chronically high antigen load probably results from antigen-specific T cells being driven to proliferate and lose IL-2 secretory capacity as they acquire effector function. The fact that loss of antigen-specific proliferation on persistent exposure to HIV can be restored with in vitro addition of IL-2 suggests that T cells lose their ability to secrete IL-2 rather than being functionally unresponsive or deleted [12, 16]
Different IFN-γ/IL-2 profiles have also been observed within single disease models, reflecting the in vivo status of the infection (e.g., a predominance of CD4 T cells secreting only IFN-γ in HIV-1–infected patients with progressive disease versus a polyfunctional IFN-γ/IL-2 response in patients with nonprogressive disease and low or undetectable viral loads [11, 12]). Furthermore, polyfunctional CD4 T cell responses are better maintained in HIV-2 infection, which, compared with HIV-1 infection, is characterized by lower viral loads and delayed disease progression [17]. Thus, a polyfunctional HIV-specific T cell response correlates with control of HIV infection. Moreover, in an infection, functional profiles are dynamic in response to changes in antigen levels, with a decrease noted in the proportion of T cells secreting only IFN-γ after treatment of TB or HIV-1 infection [11, 13–15] and an increase noted in this cell population during interruption of HIV treatment [11]. The relationship between polyfunctional T cell responses and protective immunity has not been systematically assessed in human infections other than HIV infection
Defining a correlate of protective immunity against TB would greatly accelerate the development of better interventions to control the global TB epidemic; however, to date, no correlate has been identified. The single most potent and prevalent risk factor for progression from latent MTB infection to active TB is HIV coinfection. The World Health Organization estimated that, in 2005, 11% of the 8.8 million persons with incident TB were HIV infected [18]. HIV coinfection greatly increases the risk of developing active TB, and this risk increases as HIV infection progresses, as measured by a decrease in the CD4 cell count, indicating that MTB-specific protective immunity is compromised by advancing HIV infection [19]. Studying MTB-specific immunity in persons coinfected with HIV is therefore a good model in which to search for a correlate of protective immunity
In this issue of the Journal Day and colleagues [20] exploited this clinical model and moved beyond measurement of IFN-γ alone by simultaneously analyzing multiple cytokines secreted by MTB-specific CD4 and CD8 T cells from HIV-1–positive individuals with latent MTB infection, assessing the impact of differences in HIV-1 load on MTB-specific immune responses. Fifty-six of 137 HIV-1–infected subjects who underwent screening were identified as having latent infection with MTB, on the basis of a positive IFN-γ ELISPOT response to the MTB-specific antigens early secretory antigen target 6 and/or culture filtrate protein 10. Analysis of cytokine production by MTB-specific T cells at the single-cell level indicated that, among the 40 HIV-1–infected patients with latent MTB infection who were studied, there were no differences in the median frequencies of IFN-γ–, tumor necrosis factor (TNF)–α–, or IL-2–secreting CD4 cells. Simultaneous analysis of 2 cytokines at the single-cell level showed that the majority of MTB-specific CD4 T cells were polyfunctional (i.e., either IFN-γ+/TNF-α+ or IFN-γ+/IL-2+) and that the proportion of IFN-γ+/TNF-α+ cells was significantly higher than the proportion of IFN-γ+/IL-2+ cells. Similarly, the median frequency of MTB IFN-γ– and TNF-α–secreting CD8 cells in 14 HIV-1–infected patients with latent MTB infection was significantly higher than the median frequency of IL-2–secreting CD8 cells, with the majority of cells IFN-γ+/TNF-α+ or IFN-γ+/IL-2−. Phenotyping of MTB-specific TNF-α–secreting cells suggested that these cells were effector memory T cells with an early to intermediate differentiated phenotype. Whereas MTB-specific IFN-γ–secreting T cells did not correlate with the HIV-1 load, there was a moderate inverse correlation between the proportion of MTB-specific IL-2–secreting (IFN-γ+/IL-2+ and IFN-γ−/IL-2+) CD4 cells and the HIV-1 load
This novel finding implicates CD4 T cells secreting either IL-2 only or IL-2 and IFN-γ as a potential correlate of protective immunity to TB. Because the present study lacked an HIV-uninfected control group with latent MTB infection, comparisons of MTB-specific polyfunctional T cell responses between HIV-negative and HIV-positive persons are now required to further assess the impact of HIV coinfection on immunity to MTB infection. Nonetheless, this is an important piece of research in a highly relevant population, assessing the impact of one pathogen on immunity to a different pathogen in a field that is moving beyond IFN-γ. The mechanism through which the HIV load has an impact on MTB-specific T cells is unknown. It will be interesting to determine whether the observed phenomenon is a result of a direct effect of the virus on MTB-specific T cells or is mediated via MTB-infected macrophages or other routes. The possible role for MTB-specific CD4 T cells secreting either IL-2 only or IL-2 and IFN-γ in providing protective immunity to TB now merits prospective validation in cohort studies of latently infected HIV-positive persons, to correlate the proportions of polyfunctional T cells with clinical outcomes over time (i.e., the development of active TB versus persistent asymptomatic latent TB)
The observation that distinct T cell function profiles correlate with different antigen loads [11–13] provides the immunologic rationale for application of these measures as new tools in research and in the clinic. For example, functional signatures could be used for surveillance of latent infection in vulnerable populations at high risk of progression to active TB, to monitor the effect of treatment on infection and disease, or to evaluate the performance of new drugs and new therapeutic vaccines in clinical trials. The minimum number of T cell functions that need to be assessed to achieve adequate clinical monitoring is not yet known, but, on the basis of published data, the IFN-γ/IL-2 functional signature is the most promising to date. Finally, identification of a functional signature that correlates with protective immunity would greatly aid the evaluation and development of a preventive vaccine, and the article by Day et al. [20] is a significant step in this direction
Footnotes
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Potential conflicts of interest: A.L. and K.A.M. are inventors with several patents underpinning T cell–based diagnosis and monitoring. The Lalvani interferon-γ enzyme-linked immunospot (ELISPOT) assay was commercialized into T-SPOT.TB by an Oxford University spin-out company, Oxford Immunotec, in which A.L. and Oxford University have a share of equity
- Received December 18, 2007.
- Accepted December 19, 2007.
- © 2008 by the Infectious Diseases Society of America
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