Mycobacterium tuberculosis‐specific CD8⁺ T cells are functionally and phenotypically different between latent infection and active disease

Abstract

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8 + T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8 + T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8 + T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8 + T cells in LTBI subjects were mostly T EMRA cells (CD45RA + CCR7 − ), coexpressing 2B4 and CD160, and in TB patients were mostly T EM cells (CD45RA − CCR7 − ), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8 + T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8 + T cells expressed perforin and granulysin. Finally, Mtb-specific CD8 + T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8 + T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8 + T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response.Keywords: Active TB disease r Cytotoxicity r Functional profile r Latent Mtb infection r Mtb-specific CD8 + T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2013Immunol. . 43: 1568Immunol. -1577 Immunity to infection 1569 IntroductionOne-third of the world's population is believed to be latently infected with Mycobacterium tuberculosis (Mtb) and two million people die of tuberculosis (TB) every year [1], thus underscoring the tremendous need for protective vaccines, new diagnostic tools, and medications. T lymphocytes are thought to play an important role in the control of TB and Mtb may reactivate under certain conditions of immunodeficiency such as in elderly or secondary to coinfection with HIV or to immunosuppressive therapy [2,3]. Several studies have underscored the essential role of CD4 + T cells in protection against Mtb, since CD4 + T-cell depletion is also associated with Mtb reactivation in HIV-infected individuals [4] and uncontrolled bacilli growth [5,6]. The protective Mtb-specific CD4 + T-cell response is considered to be a typical T H 1 response with CD4 + T cells producing cytokines such as IFN-γ or TNF-α that contribute to the recruitment of monocytes and granulocytes and activate the antimicrobial activity of macrophages [7,8]. Of interest, we recently demonstrated that Mtb-specific CD4 + T-cell responses were functionally different in patients with active TB disease as compared with those in subjects with latent Mtb infection (LTBI) [9]. Several studies also suggested a role of T H 17 cells in the con...

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…1C), thus indicating a shift to terminal differentiation among total CD8 + T cells in coinfected patients. These results are in line with the effect of Mtb infection on CD8 + T-cell differentiation toward an effector phenotype proposed previously [11].In order to establish whether the differences observed in circulating effector/memory subset proportions occurred due to alterations in the differentiation path, we evaluated transitions between effector/memory subsets by analyzing the correlation between phenotype proportions as described elsewhere [21,24]. A statistically significant negative correlation between the proportions of two given subsets suggests that transitions between those populations are likely to occur.…”

“…At present, this is the first report addressing Mtb-specific cytotoxic CD8 + T-cell responses and their memory status in HIV-TB coinfected patients. In TB patients, Rozot et al ascertained that Mtb-specific CD8 + T cells were mostly T EM cells [11]. On the other hand, Caccamo et al studied the phenotype of Mtb-specific CD8 + T cells by tetramer staining in TB patients, and observed a predominance of T CM and lower T TE CD8 + T cells, both of which were reverted after anti-TB therapy [37].…”

“…In this regard, while Mtb-specific CD8 + T cells in HIV neg -LTB patients are mostly composed of T TE cells (CCR7 neg /CD45RA + ), less differentiated effector memory T cells (T EM , CCR7 neg /CD45RA neg ) predominate among Mtb-specific CD8 + T cells in HIV neg -active TB patients [11]. Likewise, it has been recently found that cytokine-producing Mtb-specific CD8 + T cells from HIV-LTB, but not HIV-TB coinfected patients, also exhibited higher T TE frequencies [12], suggesting a protecting role for CD8 + T-cell terminal differentiation against TB.…”

Differences in T‐cell responses between Mycobacterium tuberculosis and Mycobacterium africanum‐infected patients

“…Although most reports on host immune responses to TB have focused on CD4 + , CD8 + T cells are important for long-term responses [33,34]. Interestingly, in this study, CD8 + T cells showed the greatest differential responses between the groups before treatment suggesting that they might be more sensitive to changes in the bacteria load with treatment than CD4 + T cells as previously shown [25,34].…”

“…Interestingly, this profile was mycobacterialantigens-specific as stimulation with PHA (mitogen) showed no differences between the groups. A higher proportion of single-TNF-α producing CD4 + and CD8 + T cells in active TB patients compared with latent TB infected (LTBI) or treated patients is well documented, with high single-TNF-α production associated with active TB disease [18][19][20][21][22][23][24][25]. TNF-α controls MTBC infection progression to disease as evidenced by the increase incidence of active TB in patients treated with anti-TNF-α [26,27].…”