IL-10 production from dendritic cells is associated with DC SIGN in human leprosy.

The defective antigen presenting ability of antigen presenting cells (APCs) modulates host cytokines and co-stimulatory signals that may lead to severity of leprosy. In the present study, we sought to evaluate the phenotypic features of APCs along with whether DC SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin) influences IL-10 production while moving from tuberculoid (BT/TT) to lepromatous (BL/LL) pole in leprosy pathogenesis. The study revealed an increased expression of DC SIGN on CD11c⁺ cells from BL/LL patients and an impaired form of CD83 (∼50 kDa). However, the cells after treatment with GM-CSF+IL-4+ManLAM showed an increased expression of similar form of CD83 on DCs. Upon treatment with ManLAM, DCs were found to show increased nuclear presence of NF-κB, thus leading to higher IL-10 production. High IL-10 production from ManLAM treated PBMCs further suggested the role of DC SIGN in subverting the DCs function towards BL/LL pole of leprosy. Anti-DC SIGN treatment resulting in restricted nuclear ingression of NF-κB as well as its acetylation along with enhanced T cell proliferation validated our findings. In conclusion, Mycobacterium leprae component triggers DC SIGN on DCs to induce production of IL-10 by modulating intracellular signalling pathway at the level of transcription factor NF-κB towards BL/LL pole of disease.

Differential development of CD4 and CD8 cytotoxic T cells (CTL) in PBMC across the leprosy spectrum; IL-6 with IFN-gamma or IL-2 generate CTL in multibacillary patients.

In the present study we evaluated the contribution of CD4 and CD8 T cells on the antigen-specific cytotoxic activity induced by whole Mycobacterium leprae in leprosy patients and normal controls (N) as well as the modulation of this activity by some cytokines. Peripheral blood mononuclear cells (PBMC) from N or from leprosy patients were stimulated with antigen in the presence or absence of cytokines for 7 days. M. leprae-stimulated PBMC were depleted of CD4 or CD8 antigen-bearing cells and employed as effector cells in a 4-hr [31Cr]-release assay against autologous M. leprae-pulsed macrophages. Our results demonstrate that both CD4 and CD8 T cells contribute to M. leprae-induced cytotoxic activity, with differences observed in paucibacillary (PB) and multibacillary (MB) patients. CD8-mediated cytotoxic activity is higher than that of CD4 cells in PB patients, while in MB patients CD4 cytotoxicity is predominant. Our data also demonstrate that the generation of CD4 and CD8 cytotoxic T lymphocytes (CTL) can be modulated differentially by interleukin-4 (IL-4), IL-6, gamma interferon (IFN-gamma), or IL-2. Although MB patients developed the lowest CTL response, cytokines such as IL-6 plus IL-2 or IFN-gamma were able to generate both CD4 and CD8 cytotoxic T cells from MB patients. In PB patients, IL-6 plus IFN-gamma displayed the highest stimulation on CD8 effector cells. Thus, an important role may be assigned to IL-6, together with IL-2 or IFN-gamma, in the differentiation of M. leprae-specific CTL effector cells.

IL-12 regulates T helper type 1 cytokine responses in human infectious disease.

We investigated the role of IL-12 in regulating T cell and cytokine responses in human infectious disease by using the spectrum of leprosy as a model. Tuberculoid patients mount strong T cell responses to Mycobacterium leprae, with production of the type 1 cytokines IL-2 and IFN-gamma in lesions; whereas lepromatous patients manifest weak T cell responses to M. leprae, with production of the type 2 cytokines IL-4 and IL-10 in lesions. We found expression of IL-12 p40 mRNA, as measured by PCR amplification, and IL-12 p70, as measured by immunohistochemistry, to be 10-fold greater in tuberculoid lesions than in lepromatous lesions. The ability of M. leprae to stimulate release of IL-12 from monocytes was inhibited by rIL-4 and rIL-10. M. leprae-induced T cell proliferation in tuberculoid patients was blocked by the addition of neutralizing Abs to IL-12. Furthermore, rIL-12 stimulated proliferation of CD4+ type 1 T cell clones from tuberculoid lesions, but not CD8+ type 2 T cell clones from lepromatous lesions; however, both responded to rIL-2, rIL-12 augmented M. leprae-specific T cell proliferation in lepromatous patients, thereby causing the selective expansion of CD4+ T cells and increasing T cell IFN-gamma production. These data indicate that IL-12 is an important mediator in the generation of the type 1 cytokine response in human infectious disease.

A comparative study on the effects of rIL-4, rIL-2, rIFN-gamma, and rTNF-alpha on specific T-cell non-responsiveness to mycobacterial antigens in lepromatous leprosy patients in vitro.

We have studied lepromatous leprosy (LL) as a human model disease for T-cell non-responsiveness to specific mycobacterial antigens and studied the effect of rIL-4, rIL-2, rIFN-gamma and rTNF-alpha thereon. T-cell non-responsiveness to Mycobacterium bovis bacillus Calmette-Guerin (BCG) or purified protein derivative of M. tuberculosis (PPD) antigens could be overcome in 5 out of 8 non-responder patients by rIL-2 and in 2 out of 8 by rIL-4. The ability of rIL-4 to overcome BCG/PPD non-responsiveness was strongly dose-dependent. When rIL-2 and rIL-4 were added simultaneously, they seemed to synergize in their effect. T-cell non-responsiveness to M. leprae could be overcome only in 2 out of 18 non-responders by rIL-2 but not by rIL-4 alone. The ability of rIL-2 to overcome T-cell non-responsiveness to M. leprae antigens became particularly marked when the recombinant 65-kDa heat shock antigen of M. leprae was used instead of whole bacilli. Exogenously added rIL-4, and to a lesser extent rIL-2, strongly enhanced existing T-cell responses to BCG or M. leprae in the majority (8 out of 11) of responders. These findings may have implications for the in vivo manipulation of the immune response by recombinant lymphokines and vaccines.