Antigen-specific T-cell Activation Distinguishes between Recent and Remote Tuberculosis infection

by Samar Abrahams

Introduction:

Mycobacterium Tuberculosis (Mtb) remains the number one killer in South Africa, with insufficient diagnostics and treatment contributing to the high mortality rates. With limited resources and the number of deaths reaching 58,000 individuals in 2019, it is imperative that all cases are detected, and that treatment is allocated to those most at risk of active Tb disease (ATB).

In this study the authors aimed to identify a blood-based biomarker that can be used in a simplified assay to measure risk of progression to active TB disease (ATB) and that can classify different stages of TB infection (TBI) that confer an increased risk of ATB-progression.

TB thrives in poverty-stricken areas where resources are limited. Thus, this study addresses a very important issue as it will allow for the identification of Mtb-infected individuals who are likely to progress to ATB (TB-progressors) and thus permits the prioritization of TB-preventative therapy (TPT) to this high-risk cohort.

Furthermore, none of the currently available TB diagnostic tests can detect TBI individuals that are likely to progress to ATB as the tests are unable to differentiate between recent infection (likely to progress to ATB) and persistent infection (low risk of progression). In addition, the identification of a blood-based biomarker presents an appealing alternative to traditional sputum-based tests.

In this study the authors focused on the expression of the T cell activation marker, HLA-DR, on Mtb-specific T cells and its potential as a blood-based biomarker. The authors hypothesized that more recent TB-infection would yield higher levels of activated Mtb-specific T cells compared to that of remote TBI and thus there would be increased expression of HLA-DR during recent infection which would signify increased risk of ATB-progression.

Methods:

Adolescents and adults were recruited for the study and divided into groups according to the following table:

Peripheral blood mononuclear cells samples were collected from the participants, stimulated, stained, and analyzed using flow cytometry. ∆HLA-DR Medium fluorescent intensity (MFI) was then measured for the test cohort and TB progressor cohort in a blinded and unblinded analysis, respectively.

Results & Conclusion:

Results generated from the test cohort revealed that HLA-DR expression on Mtb-specific CD4+ T cells, was able to effectively differentiate between those with recent QuantiFERON-TB positive (QFN+) conversion and persistent QFT+ individuals as well as persistent infection and recently diagnosed ATB. Furthermore, results from the TB-progressor cohort revealed that HLA-DR expression was also able to distinguish which TBI infected individuals were likely TB-progressors or non-progressors, with HLA-DR expression on Mtb-specific T cells being upregulated in likely TB-progressors and recent Mtb-infection.

From these results it can be deduced that HLA-DR expression on Mtb-specific CD4+ T cells is a promising biomarker candidate that can be measured and used as a screening test to identify individuals with recent infection and likely TB-progressors, thus enabling the allocation of TPT to this high-risk cohort. Provision of TPT to likely TB-progressors, is essential in middle to low-income areas where TB is endemic and thus distribution of TPT to all TB-exposed individuals is not feasible.

Furthermore, given that HLA-DR is a blood-based biomarker, it presents with an easily accessible and readily available sample. Thus, such a blood-based test can be applied to a broader category of TB-patients, such as those with extra pulmonary TB for which sputum-based tests are not applicable.

The use of HLA-DR MFI biomarker as a screening test can be combined with further clinical investigations to prioritize TPT with the goal of mitigating the TB burden in resource limited areas.

Notes to the reader:  

  1. QuantiFERON-TB is a test that measures IFN-y which is a cytokine produced by sensitized T cells in response to Mtb-antigen exposure. When a patient has a persisting QFN+ test it is an indication of persistent infection. 
  2. HLA-DR is an MHC class 2 molecule expressed on the cell surface and is involved in antigen presentation to elicit an immune response. HLA-DR is also expressed by CD4+ T helper cells and in this case, it serves as a correlate of T cell activation.

References:

  1. Mpande, C., Musvosvi, M., Rozot, V., Mosito, B., Reid, T., Schreuder, C., Lloyd, T., Bilek, N., Huang, H., Obermoser, G., Davis, M., Ruhwald, M., Hatherill, M., Scriba, T., Nemes, E., Mahomed, H., Hanekom, W., Kafaar, F., Workman, L., Mulenga, H., Ehrlich, R., Erasmus, M., Abrahams, D., Hawkridge, A., Hughes, E., Moyo, S., Gelderbloem, S., Tameris, M., Geldenhuys, H. and Hussey, G., 2021. Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection. American Journal of Respiratory and Critical Care Medicine, 203(12), pp.1556-1565.

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