Region of Difference 1 Antigen–Specific CD4+ Memory T Cells Correlate with a Favorable Outcome of Tuberculosis
1Second Division of Infectious Diseases of the Health Department, 2Translational Research Unit, and 3Laboratory of Cellular Immunology and 4Epidemiology Unit, Department of Experimental Research, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Institute for Hospitalization, Care, and Scientific Research, Rome, Italy
Background.
Interferon (IFN)–γ response to region of difference (RD) 1 proteins (culture filtrate 10 and early secreted antigenic target 6) or overlapping peptides is a novel diagnostic marker of tuberculosis (TB) infection. Because we have recently shown that the response to certain peptides selected from RD1 allows discrimination between active TB (A‐TB) and successfully treated TB (T‐TB), we analyzed here the effector memory T cell profile and RD1‐specific responses under the same clinical conditions.
Methods.T cell responses to RD1 antigens were analyzed in patients with either severe or mild A‐TB (classified on the basis of radiological lesions) and in 2 sets of healthy control subjects—those who had been successfully treated (the T‐TB control subjects) and those whose tuberculin skin test (TST) results were negative (the TST‐negative control subjects). IFN‐γ–producing CD4+ effector T cells were monitored by flow‐cytometric analysis and ex vivo enzyme‐linked immunospot (ELISPOT) assay, whereas a “cultured” ELISPOT assay was used to determine the frequency of memory T cells.
Results.In the patients with severe A‐TB, both CD4‐mediated effector memory and central memory responses to the selected RD1 peptides were almost absent, whereas these responses were found in the majority of the patients with mild A‐TB. In contrast, recognition of the selected RD1 peptides was detected in the T‐TB control subjects only by expanding the central memory T cell pool.
Conclusions.These data suggest a protective role for RD1 peptide–specific CD4+ effector T cells, which undergo clonal expansion during Mycobacterium tuberculosis replication and then a contraction phase after disease resolution, culminating in the generation of CD4+ memory T cells.
Received 19 March 2006; accepted 26 May 2006; electronically published 30 August 2006.
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Online publication date: 1-Jul-2009.
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Online publication date: 1-Jan-2009.
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Online publication date: 1-Jan-2009.
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Potential conflicts of interest: D.G., R.C., F.P., and E.G. (along with other investigators) have a patent pending on a T cell assay that is based on the selected RD1 peptides.
Financial support: Italian Ministry of Health (grant to the study); “Fondo per gli Investimenti della Ricerca di Base”–”Ministero dell'Istruzione, dell'Università e della Ricerca” (FIRB‐MIUR; grant RBNE01PPTF_003); RTD European Union Project 6th Framework Programme (project acronym, TB‐VAC; grant LSHP‐CT‐2003‐503367 to F.P.).