Decreased Expression of CD3ζ and Nuclear Transcription Factor κB in Patients with Pulmonary Tuberculosis: Potential Mechanisms and Reversibility with Treatment

Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 12/2006; 194(10):1385-93. DOI: 10.1086/508200
Source: PubMed


The protective immune response against Mycobacterium tuberculosis relies both on antigen-presenting cells and on T lymphocytes. In patients with different forms of tuberculosis, varying degrees of T cell function--ranging from positive delayed-type hypersensitivity, in asymptomatic infected healthy individuals, to the absence of the response, in patients with miliary or pulmonary tuberculosis (PTB)--have been reported. The decreased expression of CD3zeta reported in T cells from patients with either cancer or leprosy has provided possible explanations for the altered immune response observed in these diseases.
The present study aimed to compare the expression of CD3zeta , nuclear transcription factor- kappa B (NF- kappa B), arginase activity, and cytokine production in 20 patients with PTB, in 20 tuberculin-positive asymptomatic subjects, and in 14 tuberculin-negative control subjects.
Compared with those in tuberculin (purified protein derivative)-negative control subjects, peripheral-blood T lymphocytes from patients with active PTB had significantly (P < .001) decreased expression of CD3zeta and absence of the p65/p50 heterodimer of NF- kappa B. These alterations were reversed only in patients who responded to treatment. Also reported here for the first time is that the presence of arginase activity in peripheral-blood mononuclear-cell lysates of patients with PTB parallels high production of interleukin-10.
The presence of arginase could, in part, explain the decreased expression of CD3zeta . These findings provide a novel mechanism that may explain the T cell dysfunction observed in patients with PTB.

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    • "Mechanistically, the immunomodulatory activity present in MDSCs has been principally attributed to the expression of arginase and nitric oxide synthase [24,27]. Arginine depletion leads to decreased T cell expression of CD3ζ in tuberculosis and cancer patients [45-48], and can cause T cell growth arrest [49]. In the current tuberculosis murine models, arginase activity correlated with the development of lung necrosis and the presence of Gr1int cells. "
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    • "Recently, the metabolism of L-arginine by arginase has emerged as a crucial mechanism for the regulation of immune responses: increased catabolism of L-arginine by arginase results in the depletion of L-arginine from the microenvironment; since L-arginine is essential for efficient T cell activation, this decrease in L-arginine results in impaired T cell responses [7], [8], [9], [10]. Increased arginase activity has been described in malaria [11], tuberculosis [12], leishmaniasis [13], [14], [15] and HIV [16], [17]. "
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    • "For proper T-cell activation, signalling by TCR and CD28 is required and any alteration in this could lead to T-cell anergy [11]. Though altered T-cell signalling have been reported in tuberculosis [12]), and leprosy [13-15], whereas effect of lipid antigens (Man-LAM and PGL-1) on TCR/CD28- induced signalling, needs a detailed study. Previously, we have demonstrated the response of crude M. leprae antigens on the signalling mechanism of T-cells [16] therefore, current study was done to decipher the mechanism of Man-LAM and PGL-1, the lipid components, on signalling events leading to T-cell activation, which still needs documentation. "
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    ABSTRACT: Advanced stages of leprosy show T cell unresponsiveness and lipids of mycobacterial origin are speculated to modulate immune responses in these patients. Present study elucidates the role of phenolicglycolipid (PGL-1) and Mannose-capped lipoarabinomannan (Man-LAM) on TCR- and TCR/CD28- mediated signalling. We observed that lipid antigens significantly inhibit proximal early signalling events like Zap-70 phosphorylation and calcium mobilization. Interestingly, these antigens preferentially curtailed TCR-triggered early downstream signalling events like p38 phosphorylation whereas potentiated that of Erk1/2. Further, at later stages inhibition of NFAT binding, IL-2 message, CD25 expression and T-cell blastogenesis by PGL-1 and Man-LAM was noted. Altogether, we report that Man-LAM and PGL-1 preferentially interfere with TCR/CD28-triggered upstream cell signalling events, leading to reduced IL-2 secretion and T-cell blastogenesis which potentially could lead to immunosupression and thus, disease exacerbation, as noted in disease spectrum.
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