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Summary Background Previous studies suggest that control of Mycobacterium tuberculosis infection is compromised by the activity of regulatory T cells, including those that express CD39, an ectonucleotidase with immunosuppressive properties. Here, we examine the role of CD39 on CD4+ T cells reacting to M. tuberculosis antigens. Methods Cryopreserved PBMC from patients with active TB (n = 31) or individuals with LTBI (n = 30) were cultured with PPD, ESAT-6 or CFP-10 and antigen-reactive CD4+ T cells assessed by: A) intracellular expression of interferon-gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-2, B) co-expression of CD25 and CD134 with or without CD39, and C) production of IFN-γ, TNF-α and IL-10 in culture supernatants. Results Active TB patients were not differentiated from individuals with LTBI by intracellular expression of IFN-γ, TNF-α or IL-2 (alone or together), nor by co-expression of CD25 and CD134. However, active TB patients exhibited higher proportions of CD25+, CD134+, CD4+ T cells expressing CD39 in response to all antigens (p ≤ 0.022). Furthermore, in response to PPD, CD39 expression on CD25+, CD134+, CD4+ T cells correlated with IL-10 production (r = 0.41, p = 0.005) and inhibition of CD39 decreased IL-10 production. Conclusions Antigen-reactive CD4+ T cells expressing CD39 are more abundant in active TB than LTBI and are associated with production of the immunosuppressive cytokine IL-10. Modulating the effects of CD39 might enhance cellular immune responses against M. tuberculosis. [ABSTRACT FROM AUTHOR]