T-Cell Immunophenotyping Distinguishes Active From Latent Tuberculosis

Abstract

Background. Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection.Methods. A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α).Results. Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPD-specific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone.Conclusions. Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies.

Differences in T‐cell responses between Mycobacterium tuberculosis and Mycobacterium africanum‐infected patients

“…Interestingly, this profile was mycobacterialantigens-specific as stimulation with PHA (mitogen) showed no differences between the groups. A higher proportion of single-TNF-α producing CD4 + and CD8 + T cells in active TB patients compared with latent TB infected (LTBI) or treated patients is well documented, with high single-TNF-α production associated with active TB disease [18][19][20][21][22][23][24][25]. TNF-α controls MTBC infection progression to disease as evidenced by the increase incidence of active TB in patients treated with anti-TNF-α [26,27].…”

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…Phenotyping of immune cells using this approach has shown that different T-cell subsets can differentiate between latent and active TB. Mtb-specific CD4 þ and CD8 þ T-cell subsets secreting TNF-a only, IFN-g only, and dual TNFa/IFN-g appear in higher frequencies in TB patients compared with latently infected individuals (Pollock et al 2013). CD4 þ T cells from individuals latently infected are polyfunctional and express TNF-a, IFN-g, and IL-2 compared with the dominant TNF-a-only response of TB patients (Harari et al 2011).…”

“…CD4 þ T cells from individuals latently infected are polyfunctional and express TNF-a, IFN-g, and IL-2 compared with the dominant TNF-a-only response of TB patients (Harari et al 2011). During active disease, Mtb-specific CD4 þ T cells also switch from central to effector memory T cells, which are accompanied by a decrease in IL-7 receptor a expression (Pollock et al 2013). PPD-specific TNF-a-only secreting CD4 þ T cells with an effector memory phenotype might therefore discriminate active disease and latent TB infection (LTBI) with promising accuracy.…”

Mycobacterium bovis induce una respuesta inmune celular heterogénea en bovinos infectados naturalmente

“…Es importante puntualizar que la respuesta inmune contra la tuberculosis es un proceso muy complejo (1,8,26) . Como se mencionó al inicio, después de la exposición inicial a M. bovis, se desarrolla una respuesta inmune celular T, pero para controlar la proliferación bacteriana se requiere un equilibro muy fino entre la producción de citocinas pro y antiinflamatorias.…”

“…Así mismo, se sabe que diferentes tipos de subpoblaciones de linfocitos T participan en la respuesta inmune contra las micobacterias. Diversos estudios han demostrado que personas con una infección latente de tuberculosis muestran mayores frecuencias de linfocitos T CD4 + trifuncionales, capaces de producir IFN-γ, TNF-α e IL-2, con una mayor capacidad efectora y proliferativa (30) , en contraste con personas con la enfermedad activa que muestran frecuencias elevadas de linfocitos T CD4 + con función simple o doble (26) . Por lo tanto, es posible que la polifuncionalidad pueda correlacionarse con la resistencia a la tuberculosis en humanos y bovinos (31) .…”