Abstract
Multifunctional T cells have been shown to be protective in chronic viral infections. In mycobacterial infections, however, evidence for a protective role of multifunctional T cells remains inconclusive. Short-term cultures of peripheral blood mononuclear cells stimulated with the Mycobacterium tuberculosis RD1 antigens 6-kDa early secretory antigenic target (ESAT6) and 10-kDa culture filtrate antigen (CFP10), which are induced in the early infection phase, have been mainly used to assess T cell multifunctionality, although long-term culture assays have been proposed to be more sensitive than short-term assays for assessment of memory T cells, which are essential for long-term immunity. Here we used a long-term culture assay system to study the T cell immune responses to the M. tuberculosis latency-associated DosR antigens and reactivation-associated Rpf antigens, compared to ESAT6 and CFP10, in patients with pulmonary tuberculosis (PTB) and household contacts of PTB patients with long-term latent tuberculosis infection (ltLTBI), in a community in which M. tuberculosis is endemic. Our results showed that the DosR antigens Rv1737c (narK2) and Rv2029c (pfkB) and the Rv2389c (rpfD) antigen of M. tuberculosis induced higher frequencies of CD4+ or CD8+ mono- or bifunctional (but not multifunctional) T cells producing interferon gamma (IFN-γ) and/or tumor necrosis alpha (TNF-α) in ltLTBI, compared to PTB. Moreover, the frequencies of CD4+ and/or CD8+ T cells with a CD45RO+ CD27+ phenotype were higher in ltLTBI than in PTB. Thus, the immune responses to selected DosR and Rpf antigens may be associated with long-term latency, correlating with protection from M. tuberculosis reactivation in ltLTBI. Further study of the functional and memory phenotypes may contribute to further discrimination between the different states of M. tuberculosis infections.
Highlights
T cells capable of simultaneously producing two or three cytokines have been described in recent years
We found that Rv1737c (NarK2), Rv2029c (PfkB), and Rv2389c (RpfD) antigens induced higher frequencies of CD4ϩ or CD8ϩ mono- or bifunctional T cells
Higher frequencies of bifunctional CD4ϩ or CD8ϩ T cells with a TEM phenotype (CD45ROϩ CD27Ϫ) in response to RD1, DosR, and resuscitation-promoting factors (Rpfs) antigens were observed in pulmonary tuberculosis (PTB), compared with long-term latent tuberculosis infection (ltLTBI)
Summary
T cells capable of simultaneously producing two (bifunctional) or three (multifunctional) cytokines have been described in recent years. A higher frequency of multifunctional CD4ϩ T cells, producing IFN-␥, TNF-␣, and IL-2, in peripheral blood mononuclear cells (PBMCs) from patients with active pulmonary tuberculosis (PTB), compared to individuals with latent TB infection (LTBI), was reported [15,16,17] and decreased following anti-TB treatment [16, 17]. Multifunctional T cell response to DosR and Rpf antigens is associated with protection in long-term Mycobacterium tuberculosis-infected individuals in Colombia. Different studies have shown that individuals with LTBI display greater frequencies of TCM cells upon in vitro stimulation with RD1 antigens and purified protein derivative (PPD), compared to PTB patients, in long-term culture assays [23,24,25]. Individuals with LTBI, compared to PTB patients, preferentially recognize resuscitation-promoting factors (Rpfs) [34, 36, 40,41,42], proteins known to participate in bacterial reactivation from a quiescent state and to be present in M. tuberculosis [43, 44]
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