Clinical Significance of Interleukin-2/Gamma Interferon Ratios in Mycobacterium tuberculosis-Specific T-Cell Signatures

Abstract

The simultaneous determination of interleukin-2 (IL-2) and gamma interferon (IFN-␥) in Quanti-FERON-TB test plasma supernatants permitted the detection of shifts in Mycobacterium tuberculosis-specific T-cell signatures. A subset of the 84 subjects tested revealed a significantly elevated IL-2/IFN-␥ ratio, which may be a marker for the successful elimination of M. tuberculosis infection.In countries with low tuberculosis (TB) incidence rates, such as Switzerland, targeted testing for latent Mycobacterium tuberculosis infection (LTBI) among risk groups, such as health care workers (HCW), is an important measure for preventing active TB disease (3, 7). Occupational health programs are increasingly turning to gamma interferon (IFN-␥) release assays (IGRA), such as the QuantiFERON-TB Gold in-tube test (QFT test; Cellestis Inc., Australia), to screen employees for LTBI (4,5,9). Diel et al. prospectively followed QFT testpositive, recent-TB contacts who had refused isoniazid treatment. All contacts who subsequently developed active TB disease within the follow-up period were strong responders in the QFT assay, with IFN-␥ plasma levels above the 10-IU/ml upper limit for the test's enzyme-linked immunosorbent assay (ELISA) (6). These results suggest that a correlation exists between the amount of IFN-␥ released upon M. tuberculosis-specific stimulation of CD4 ϩ T cells and the probability of developing active TB disease.A dynamic relationship between antigen load and distinct IFN-␥ and interleukin-2 (IL-2) profiles of antigen-specific CD4ϩ T cells has been demonstrated in viral infections (10). Typically, antigen clearance is associated with IL-2-dominant functional T-cell signatures. In contrast, high antigen loads are associated with IFN-␥-dominant functional T-cell signatures (10). A similar relationship between the IFN-␥ and IL-2 profiles of M. tuberculosis-specific T cells and antigenic load was reported in patients who were treated for active TB disease (1,2,8). Simultaneous measurement of IFN-␥ and IL-2 secretion at the single-cell level revealed a codominance of CD4 ϩ T cells that secrete only IFN-␥ and those that secrete both IFN-␥ and IL-2 in patients with active TB disease. A shift to dominance of CD4 ϩ T cells secreting both IFN-␥ and IL-2 and of newly detectable CD4 ϩ T cells secreting only IL-2 has been demonstrated both during and following TB treatment. Thus, three main functional patterns were observed: a dominant IL-2 response, a multifunctional (IL-2 and IFN-␥) response, and a dominant IFN-␥ response. Determination of the levels of IL-2 and IFN-␥ secretion has been proposed as an adequate marker for clinical monitoring (10). The net result of functional T-cell signatures would be detectable by assessing the M. tuberculosisspecific IL-2/IFN-␥ ratio in QFT test plasma supernatants. Thus, the simultaneous analysis of both IFN-␥ and IL-2 in QFT test plasma supernatants might provide (i) a more precise basis for assessing an individual's risk of developing active TB disease and (ii) information concerning t...

Diagnostic accuracy of IL-2 for the diagnosis of latent tuberculosis: a systematic review and meta-analysis

“…Eleven out of the 16 publications [9,[17][18][19][20][21][22][23][24][25][26] dealing with IL-2 as a biomarker for the diagnosis of active and latent tuberculosis were considered to be eligible for inclusion in the qualitative analysis. For meta-analysis among these publications, six studies [4,8,10,20,27,28] were excluded because IFN-γ was detected only in patients with active tuberculosis [8], it was done in patients during and after their anti-tuberculosis treatment [10], the cytometric detection of IFN-γ-/IL-2-secreting cells was used [4,28], or they contained no detailed data [27].…”

“…This type of response has been shown to be associated with the elimination of M. tuberculosis infection and suggests that such patients may not require prophylactic therapy [10,27,32].…”

“…There were higher proportions of IL-2/IFN-γ CD4 + T-cells in LTBI or successfully treated TB subjects, which have lower bacterial loads, while in active TB, the cytokine profile was shifted towards cells secreting only IFN-γ [9,10,27,28,32].…”

“…In the study by Suter-Riniker et al [27], the simultaneous analysis of IFN-γ and IL-2 in plasma supernatants revealed a significant shift toward an IL-2-dominant functional T-cell response compared to those of the intermediate (IFN-γ, 1.0 to 5.0 IU/ml) and high (IFN-γ, >5.0 IU/ml) responders. This type of response has been shown to be associated with the elimination of M. tuberculosis infection and suggests that such patients may not require prophylactic therapy [10,27,32].…”

Diagnostic Performance of a Cytokine and IFN-γ–Induced Chemokine mRNA Assay after Mycobacterium tuberculosis–Specific Antigen Stimulation in Whole Blood from Infected Individuals

“…16e22 Other studies have shown that IFN-g alone is not sufficient to provide protection against disease progression 23 and that tumor necrosis factor (TNF)-a also is important in controlling MTB infection. 24 In addition, IL-2 was shown to correlate with pathogen load, 25 and IL-4 and IL-10 levels also were linked closely to active TB. 26 In particular, CXCL9 [also known as monokine induced by IFN-g (MIG)], was increased in plasma in patients with active PTB and tuberculous pleurisy compared with healthy controls, and secretion of IL-2, CXCL10 [IFN-g inducible protein 10 (IP-10)], and CXCL11 [IFN-inducible T-cell a chemoattractant (I-TAC)] was enhanced in LTBI individuals.…”