Massive monoclonal expansion of CD4 T-cells specific for aMycobacterium tuberculosisESAT-6 peptide

Abstract

T-cell responses towards tuberculin (purified protein derivative; PPD) or the Mycobacterium tuberculosis-specific antigens early secretory antigenic target (ESAT)-6 and culture filtrate protein-10 are indicative of prior contact with mycobacterial antigens. In this study, we investigated the exceptional case of a 75-yr-old patient who devoted more than one-third of his CD4 T-cells against PPD and ESAT-6.Antigen-specific T-cells were characterised using flow cytometric intracellular cytokine staining, ELISPOT assay, proliferation assays, and T-cell receptor spectratyping.T-cell frequencies were far above those found in age-matched controls (median 0.33%, range 0.05-6.32%) and remained at high levels for .2 yrs. The patient initially presented with haemoptysis, but active tuberculosis was ruled out by repeated analysis of sputum and bronchoalveolar lavage fluid. Skin testing was negative and haemoptyses did not have a M. tuberculosis-related aetiology. Phenotypical and functional properties of specific T-cells were consistent with a terminally differentiated effector-memory phenotype with capacity to produce interferon-c, interleukin-2 and tumour necrosis factor-a. Epitope mapping showed that the CD4 T-cells were directed against a single peptide from ESAT-6 (amino acid 5-20) that was presented in context of HLA-DR. T-cell receptor Vb-spectratyping and sequencing of specific CD4 T-cells revealed a prominent peak fraction of monoclonal origin.In conclusion, similar to monoclonal gammopathies of undetermined significance, this may represent the first T-cell counterpart with known specificity against M. tuberculosis.

Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV

“…Because previous studies of the effect of latent or active TB on immune activation have primarily characterized HIV-uninfected individuals, and because we were specifically interested in immune activation markers implicated in HIV pathogenesis, we only assessed these markers in HIV co-infected subjects. While previous studies have found no evidence for elevated immune activation (of either bulk T-cells or M. tb -specific T-cells) in latently-infected, HIV-negative individuals ( Rodrigues et al, 2002 , Wergeland et al, 2011 , De Almeida et al, 2012 , Adekambi et al, 2012 , Hodapp et al, 2012 ), our data suggest that this is not the case for HIV-infected individuals who also harbor latent TB infection. This surprising finding challenges the notion of latency as a fully dormant state of TB infection, and suggests that HIV co-infection may skew this heterogeneous state towards a state that immunologically resembles more active infection.…”

Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection

“…It has been reported that CD4 + T cell-mediated immunity plays a critical role in controlling chronic bacterial and viral infections [10,21-24]. In the present study, we showed that the use of our gene melting spectral pattern (GMSP) assay to study TCRBV gene families in PBMCs, CD4 + and CD8 + T cell subsets from subjects with active TB or LTBI was helpful in the differential diagnosis and treatment of active TB or LTBI.…”

Development of an improved ESAT-6 and CFP-10 peptide-based cytokine flow cytometric assay for bovine tuberculosis

“…It has yielded encouraging results when used to detect humans infected with M. Tuberculosis [16][17][18][19][20][21][22][23]. One major advantage of CFC is that it provides an opportunity to count the number of responding cells and simultaneously determine their Table 1 Receiver operator characteristics (ROC) analyses of antigen-specific IFN-␥ producing CD4 + T cells frequencies to distinguish between infection states.…”