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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4776-4777.
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CORRESPONDENCE
Do human   T cells respond to M tuberculosis protein antigens?
To the editor:
Recently Li et al1 reported that circulating   T cells from tuberculin skin test (TST)-positive patients respond directly in vitro to early secreted antigenic target 6 (ESAT-6) protein from Mycobacterium tuberculosis by proliferating and by producing interferon (IFN-). We think that these results do not agree with the current model of T-cell antigen (Ag) recognition and activation.
Human V9V2 T cells represent 1% to 5% of circulating lymphocytes in adults and recognize nonpeptidic phosphoantigens, metabolites of isoprenoid pathway.2,3 Although most potent phosphoantigens, such as hydroxymethylbutyl-pyrophosphate (HMBP), are produced by infectious agents and recognized as nonself, others, such as isopentenyl pyrophosphate (IPP), are normal metabolites of mammalian mevalonate pathway, and their accumulation represents a danger signal from infected or transformed cells.4 A similar mechanism explains V9V2 response to aminobisphosphonates5 and alkyl amines.6 Due to small size, phosphoantigens are physically unable to cross-link T-cell receptors (TCRs), and a complex of apolipoprotein A (ApoA) and mitochondrial adenosine triphosphatase (ATPase) was proposed as a presenting molecule.7 However, the recognition mechanism of human V9V2 TCR remains incompletely defined. Other major histocompatibility complex (MHC) class I–like molecules may stimulate human T cells: CD1c can present foreign lipids and glycolipids to V1+ T cells, a subset commonly found in humans in periphery.8
On the other hand, ESAT-6 protein is able to induce IFN- production by CD4 T lymphocytes from patients with active tuberculosis (TB) and latent TB infection (LTBI).9
To evaluate T cells' response to ESAT-6 protein, we tested 4 patients with active TB and 4 subjects with LTBI (positive to QuantiFERON TB Gold and TST). Figure 1 shows representative results from an active TB patient (Figure 1A) and a TST-positive LTBI subject (Figure 1B-D). As expected, CD4 T cells produce IFN- to ESAT-6 in active TB patients (Figure 1A) as well as in LTBI subjects (Figure 1B). Differently from Li et al,1 in the same conditions ESAT-6 failed to induce IFN- production from V2 or V1 T cells (Figure 1C,D). Accordingly, IFN- response was not associated with CD4– T cells (Figure 1A,B).9
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Figure 1. ESAT-6 protein induces  β but not T cells' response in active TB patients and TST-positive LTBI subjects. Peripheral blood mononuclear cells (PBMCs) from a representative active TB patient (A) and a representative TST-positive LTBI subject (B-D) were stimulated with ESAT-6 protein (5 µg/mL; Lionex, Braunschweig, Germany) in presence of anti-CD28 monoclonal antibody (1 µg/mL; BD Biosciences, San Jose, CA). To detect intracellular expression of IFN-, brefeldin-A (Sigma-Aldrich, St Louis, MO) at 10 µg/mL was used. After overnight stimulation, cells were stained with CD4-peridinin chlorophyll protein (PerCP), V2-phycoerythrin (PE), V1-fluorescein isothiocyanate (FITC), IFN- allophycocyanin (APC) anti–human conjugated monoclonal antibodies (BD Biosciences). For all staining procedures, an isotype-matched negative control was used. Data acquisition and analysis were performed using a FASCalibur flow cytometer and CellQuest software (both BD Biosciences).
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Since no direct specific response of T cells to protein antigen, as described by Li et al,1 is known, the proposed T-cell response to ESAT-6 should be confirmed by analyzing its dependence from a conserved protein antigen 3-dimensional conformation. Alternatively, other triggering agent(s) inducing activation of T cells could be proposed. Since, according to Li et al,1 T-cell response was linked to ESAT-6 in a dose-response manner, a contaminating phosphoantigen could be postulated in that particular ESAT-6 preparation; T-cell response should disappear if more purified (or dialyzed) ESAT-6 protein is used. Therefore, human T-cell direct response to soluble protein Ag is an unexpected result representing a new, direct nonprocessed surveillance route regarding extracellular proteins. This mechanism would be totally different from β T cells' response to protein Ag, which requires intracellular or extracellular processing and, respectively, MHC class I or II molecule presentation. If confirmed, T cells could, once again, display a unique response capability. However, in our view, this possibility deserves a more accurate evaluation.
Authorship
This study was supported by grants from Italian Health Ministry.
Conflick-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Rita Casetti, Laboratory of Cellular Immunology, National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy; e-mail: casetti{at}inmi.it.
Rita Casetti,
Angelo Martino,
Alessandra Sacchi,
Chiara Agrati,
Delia Goletti, and
Federico Martini
References
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- Hayday AC. [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol. 2000;18:975–1026.[CrossRef][Medline]
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- Chien YH, Konigshofer Y. Antigen recognition by gammadelta T cells. Immunol Rev. 2007;215:46–58.[CrossRef][Medline]
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- Morita CT, Jin C, Sarikonda G, Wang H. Nonpeptide antigens, presentation mechanisms, and immunologic memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev. 2007;215:59–76.[CrossRef][Medline]
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- Gober HJ, Kistowska M, Angman L, et al. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med. 2003;197:163–168.[Abstract/Free Full Text]
- Kabelitz D. Small molecules for the activation of human gammadelta T cell responses against infection. Recent Patents Anti-Infect Drug Disc. 2008;3:1–9.
- Scotet E, Martinez LO, Grant E, et al. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity. 2005;22:71–80.[CrossRef][Medline]
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- Russano AM, Bassotti G, Agea E, et al. CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gammadelta+ T lymphocytes. J Immunol. 2007;178:3620–3626.[Abstract/Free Full Text]
- Goletti D, Butera O, Bizzoni F, et al. Region of difference 1 antigen-specific CD4+ memory T cells correlate with a favorable outcome of tuberculosis. J Infect Dis. 2006;194:984–992.[CrossRef][Medline]
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