Parasite-specific Th1 Research Articles

The L3 of Brugia induces a Th2-polarized response following activation of an IL-4-producing CD4-CD8- alphabeta T cell population.

Lymphatic filariasis in man is characterized by a profound bias in the immune response. Parasite-specific Th1 responses are dramatically down-regulated while Th2 responses dominate. We have used the infective larval stage of the nematode parasite Brugia pahangi, a potent Th2 inducer in naive mice, to examine cytokine production during the initiation phase of the response. For comparative purposes, the early cytokine transcription pattern elicited by microfilariae (mf), another life cycle stage of the parasite known to induce a primary Th1 response, was analysed in parallel. At 24 h post-infection (p.i.) a burst of IL-4 transcription was detected in the draining popliteal lymph node of L3-infected animals. IL-4 was the only cytokine transcript detectable at this early time point and was not present in mf-infected mice. From day 4 p.i. onwards, the L3 elicited a Th2 response as defined at the level of cytokine mRNA and protein production by CD4+ cells. In contrast, mf stimulate high levels of IFN-gamma mRNA at day 4 p.i. in the absence of IL-4 or IL-10 induction. Cell selection analysis indicated that IL-4 produced at 24 h derived from a population of CD4-CD8- alphabeta T cells. These results suggest that triggering of an unusual double-negative T cell population to secrete IL-4 at the very outset of infection with the L3 of B. pahangi may be the critical factor favouring the development of antigen-specific Th2 cells in response to this stage of the parasite.

The Xid defect imparts susceptibility to experimental murine filariosis--association with a lack of antibody and IL-10 production by B cells in response to phosphorylcholine.

The pathways conferring immunity to filarial infections are not well known, in part because human pathogenic filariae do not develop a full infection cycle in laboratory mice. Using the permissive infection with Litomosoides sigmodontis in BALB/c mice, we have shown previously that worm development is controlled by CD4+ T cells and is inversely correlated with Th2 cytokine production. Here we analyzed the impact of the Xid immunodeficiency on murine filariosis, comparing the course of infection with L. sigmodontis in BALB/c and B1 cell-deficient BALB.Xid mice. In BALB.Xid mice, 2-3 times more adult worms and up to 10 times more microfilariae compared to BALB/c were observed to develop after infection with infective stage 3 larvae (L3). Parasite-specific Th2 cytokine production by cells from the thoracic cavity, the primary location of the parasites, was diminished significantly in BALB.Xid compared to BALB/c mice. In addition, BALB.Xid mice displayed a significantly lower production of antibodies and B cell-derived IL-10 in response to both L. sigmodontis antigen and phosphorylcholine, a molecule we found to be abundant on the surface of L3. Thus, the B cell-defect in BALB.Xid mice may account for susceptibility to murine filarial infection in two ways, i.e. by the lack of antibody to a dominant surface molecule of invading L3 and by less B cell-derived IL-10 resulting in lower parasite-driven Th2 cytokine production.

The fate and persistence of Leishmania major in mice of different genetic backgrounds: an example of exploitation of the immune system by intracellular parasites.

Leishmania spp. are intracellular protozoan parasites that are delivered within the dermis of their vertebrate hosts. Within this peripheral tissue and the draining lymph node, they find and/or rapidly create dynamic microenvironments that determine their ultimate fate, namely their more or less successful expansion, and favour their transmission to another vertebrate host though a blood-feeding vector. Depending on their genetic characteristics as well as the genetic make-up of their hosts, once within the dermis Leishmania spp. very rapidly drive and maintain sustained T cell-dependent immune responses that arbitrate their ultimate fate within their hosts. The analysis of the parasitism exerted by Leishmania major in mice of different genetic backgrounds has allowed us to recognize some of the early and late mechanisms driven by this parasite that lead to either uncontrolled or restricted parasitism. Uncontrolled parasitism by Leishmania major characterizing mice from a few inbred strains (e.g. BALB/c) is associated with the expansion of parasite reactive Th2 CD4 lymphocytes and results from their rapid and sustained activity. In contrast, restricted parasitism characteristic of mice from the majority of inbred strains results from the development of a polarized parasite-specific Th1 CD4 response. This murine model of infection has already been and will continue to be particularly instrumental in dissecting the rules controlling the pathway of differentiation of T cells in vivo. In the long run, the understanding of these rules should contribute to the rational development of novel immunotherapeutic interventions against severe infectious diseases.

Induction of murine T-helper-cell responses to the filarial nematode Brugia malayi.

The purpose of this study was to examine the murine T-helper-cell (Th) cytokine response to the human filarial parasite Brugia malayi. In the first 14 days following intraperitoneal inoculation of live microfilariae into BALB/c mice, filarial antigen-driven splenic lymphoid cells produced gamma interferon (IFN-gamma) and little or no interleukin-5 (IL-5). After this time, IL-5 production increased (to 10 to 12 ng per 5 x 10(6) cells) coincident with a marked diminution in IFN-gamma generation. A single subcutaneous immunization with soluble microfilarial antigens also induced an IFN-gamma but no IL-5 response, whereas immunization three times elicited a predominant Th2-like reaction characterized by IL-4 and IL-5 production by CD4+ lymph node lymphocytes and a 10-fold increase in serum immunoglobulin E. The importance of IL-10 in establishing the balance between parasite-specific Th1 and Th2 responses was demonstrated by the ability of neutralizing monoclonal antibody to this cytokine to increase IFN-gamma production by splenic and lymph node cells from mice chronically exposed to live microfilariae or immunized multiple times with soluble filarial antigens.

Reconstitution of Leishmania immunity in severe combined immunodeficient mice using Th1- and Th2-like cell lines.

Leishmania major disseminates in genetically susceptible BALB/c mice to cause fatal disease. Progressive infection has been linked to the failure of parasite-specific Th1, IFN-gamma-producing, CD4+ T lymphocytes to expand and direct macrophage activation and control of intracellular parasitism. In contrast, Th2 CD4+ cell expansion accompanies disease progression. Immunomodulation using CD4 cell depletion at the time of infection results in control of infection and Th1 CD4+ cell expansion. A Th1-like cell line, H1A, was established from the draining lymph nodes of an anti-CD4-pretreated BALB/c mouse infected with L. major, H1A was CD4, TCR(+)-alpha/beta, and released IL-2 and IFN-gamma in response to parasite Ag. A Th2-like cell line, U1A, was established from the lymph node cells of an infected BALB/c mouse that was also CD4, TCR(+)-alpha/beta but released IL-4 and IL-5 after stimulation. Mice with severe combined immunodeficiency were reconstituted with H1A and U1A before infection with L. major. Non-reconstituted mice were unable to restrict parasite growth. Mice reconstituted with H1A healed infection, whereas mice reconstituted with U1A suffered exacerbation of disease. Analysis of spleen cells by flow cytometry confirmed the reconstitution of CD4+ cells in both instances, and stimulation with mitogen established that the lymphokine profile of the donor cells had been maintained during 6 to 8 wk of infection. Histologic analysis of the lesions confirmed migration of donated cells to sites of infection. Neutralization of IFN-gamma in H1A-reconstituted mice and IL-4 in U1A-reconstituted mice reversed the disease phenotype mediated by the two cell lines. These data demonstrate the capacity of CD4+ T cells alone to modulate both positively and negatively the course of leishmaniasis in a lymphokine-dependent manner.

Analysis of the cellular parameters of the immune responses contributing to resistance and susceptibility of mice to infection with the intracellular parasite, Leishmania major.

Although the course of infection induced by L.major in mice is influenced by several factors, including the parasite virulence, the macrophage permissiveness to this parasite and response to T cell-produced lymphokines, this review has been restricted to summarizing, the recent data concerning the T-cell responses generated during infection and their effect on the disease process. Experimental evidence strongly suggests that T-cell responses play a fundamental role in resistance and susceptibility of mice to infection with L.major. It appears that resolution of lesion and exacerbation of disease result from the activity of distinct specific CD4+ T cells. There is a consensus of opinion that CD4+ T cells from the TH1 functional phenotype are generally endowed with protective function through their secreted lymphokines (e.g. IFN-gamma). However, some evidence exists that other lymphokines (e.g. TNF) might be involved in resolution of lesions. Results exist which indicate that some TH1 CD4+ T cells also contribute to susceptibility to infection. Their specificity differs from that of protective TH1 cells in the sense that these T cells might recognize parasite antigens not appropriately presented by parasitized macrophages and therefore, although releasing IFN-gamma, would not be able to concentrate this lymphokine on the surface of macrophages containing multiplying L.major. It appears that parasite-specific TH2 cells play an important role, through the IL-4 that they produce, in the severe disease seen in BALB/c mice. Determining the mechanisms responsible for the expansion of TH2 cells in genetically susceptible mice as well as assessing whether or not some parasite antigens are preferentially recognized by TH1 and TH2 cells are areas of investigation of prime importance for the rational design of a vaccine against leishmaniasis. Several observations indicate that CD8+ T cells have a role in the resolution of lesions induced by this parasite. Precise investigation of the mechanism(s) accounting for their beneficial effect might depend upon our ability to derive and maintain in vitro homogenous populations and clones of L.major-specific CD8+ T cells.