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Leishmania major-parasitized macrophages augment Th2-type T cell activation
1Department of Tropical Public Health, Harvard School of Public Health, Boston, MA 02115.
Abstract:
We studied the ability of resident peritoneal M phi, parasitized in vitro with Leishmania major, to present Ag to three Th2-type T cell clones that are specific for non-leishmanial Ags. Results indicated that L. major-infected M phi enhanced the proliferation and IL-4 secretion of Th2 T cells in response to stimulation with their cognate Ag. Augmentation of Th2 T cell proliferation was seen in Ag-driven responses but not in mitogenic Con A stimulation. Furthermore, live L. major promastigotes and amastigotes, but not killed parasites, augmented the Th2 T cell response. To delineate the augmentative effect of L. major-infected M phi for Th2 T cell activation, we analyzed the cytokines produced by infected M phi in the presence or absence of Th2 T cell clones. The supernatants contained IL-1 but not IL-6 or IL-10. Interestingly, addition of a neutralizing anti-IL-1 alpha mAb to the cultures reduced the augmentative effect for Th2 proliferation. Moreover, additional experiments showed that IL-1 alpha could substitute for L. major and enhance T cell activation in cultures consisting of Th2 cells, normal M phi, and Ag. Thus, our study shows that L. major-infected M phi present Ags in a manner that augments Th2 T cell proliferation and IL-4 synthesis, and that the phenomenon is at least in part mediated by IL-1 secreted by the infected M phi. For purposes of comparison, two non-leishmanial Ag specific Th1-type T cell clones were stimulated with L. major-infected M phi. Our data, as already reported by others, showed that infected M phi inhibited the response of Th1 T cells to their cognate Ag. Taken together, this report shows that leishmanial-infected M phi favor the activation of Th2 T cells over Th1 cells and that Th1 and Th2 cells require distinct activation signals from M phi.
Insights
Leishmania major-infected macrophages enhance T-helper 2 (Th2) cell responses, promoting their proliferation and IL-4 secretion. This effect, mediated partly by IL-1, favors Th2 over Th1 cell activation.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Macrophages (M phi) play a crucial role in immune responses by presenting antigens to T cells.
- Leishmania major infection alters macrophage function, influencing their interaction with immune cells.
- T helper (Th) cells differentiate into distinct subsets (e.g., Th1, Th2) with different functions.
Purpose of the Study:
- To investigate how Leishmania major-infected macrophages affect the activation of Th2-type T cells.
- To determine the role of cytokines, particularly IL-1, in modulating T cell responses during Leishmania infection.
- To compare the differential effects of infected macrophages on Th1 versus Th2 cell activation.
Main Methods:
- In vitro culture of resident peritoneal macrophages infected with Leishmania major.
- Co-culture of infected macrophages with antigen-specific Th2 T cell clones.
- Measurement of T cell proliferation and IL-4 secretion.
- Cytokine analysis (IL-1, IL-6, IL-10) of macrophage supernatants.
- Use of neutralizing antibodies (anti-IL-1 alpha mAb) to block cytokine effects.
- Stimulation of Th1 T cell clones with infected macrophages for comparison.
Main Results:
- Leishmania major-infected macrophages augmented antigen-driven proliferation and IL-4 secretion of Th2 T cells.
- Live, but not killed, Leishmania parasites were effective in augmenting Th2 responses.
- Interleukin-1 (IL-1) was detected in supernatants of infected macrophages, and anti-IL-1 alpha antibodies reduced the augmentation effect.
- Exogenous IL-1 alpha could substitute for infected macrophages in enhancing Th2 cell activation.
- In contrast, Leishmania major-infected macrophages inhibited the response of Th1 T cells to their cognate antigens.
Conclusions:
- Leishmania major-infected macrophages present antigens in a way that preferentially enhances Th2 cell proliferation and IL-4 synthesis.
- The augmentative effect on Th2 cells is, at least partially, mediated by IL-1 secreted by the infected macrophages.
- Leishmania-infected macrophages promote Th2 cell activation over Th1 cell activation, highlighting distinct activation requirements for these T cell subsets.