Tracking antigen-specific CD4+T cells throughout the course of chronicLeishmania majorinfection in resistant mice (original) (raw)
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European Journal of Immunology, 2012
Primary Leishmania major infection typically produces cutaneous lesions that heal but that harbor persistent parasites. While the opposing roles of CD4 + T cell-derived IFN-γ and IL-10 in promoting parasite killing and persistence have been well established, how these responses develop from naïve precursors has not been directly monitored throughout the course of infection. We used peptide:Major Histocompatibility Complex II (pMHCII) tetramers to investigate the endogenous, parasite-specific primary CD4 + T cell response to L. major in mice resistant to infection. Maximal frequencies of IFN-γ + CD4 + T cells were observed in the spleen and infected ears within a month after infection and were maintained into the chronic phase. In contrast, peak frequencies of IL-10 + CD4 + T cells emerged within 2 weeks of infection, persisted into the chronic phase, and accumulated in the infected ears but not the spleen, via a process that depended on local antigen presentation. T helper type-1 (Th1) cells, not Foxp3 + regulatory T cells, were the chief producers of IL-10 and were not exhausted. Therefore, tracking antigen-specific CD4 + T cells revealed that IL-10 production by Th1 cells is not due to persistent T cell antigen receptor stimulation, but rather driven by early antigen encounter at the site of infection.
Proceedings of the National Academy of Sciences, 2009
Recovery from natural or experimental Leishmania major infection, the causative agent of cutaneous leishmaniasis, results in development of durable immunity in mice and humans that is manifested as rapid control of parasite replication and resolution of cutaneous lesion after secondary challenge. This form of “infection-induced” immunity is thought to occur naturally in endemic areas and is generally considered the gold standard for any effective vaccine against cutaneous leishmaniasis. To determine factors that might heighten or abrogate infection-induced immunity, we investigated the impact of inoculating dead antigen in the form of killed Leishmania parasites to healed mice. We show that inoculation of killed parasites into mice that resolved their primary virulent L. major infection results in rapid and relatively sustained loss of infection-induced immunity. This loss of immunity was not due to the inability of killed parasites to induce inflammatory responses (such as delayed ...
European Journal of Immunology, 2008
Leishmaniasis is currently classified as category 1 disease, i.e. emerging and uncontrolled. Since the importance of persistent infection for maintaining an effective long-lasting protective response is controversial, the present study asks whether immunisation with non-persistent parasites leads to protection against Leishmania infection and to the recruitment of T cells of a specific phenotype. Our study shows that vaccination of susceptible BALB/c mice with live Leishmania major phosphomannomutase-deficient parasites, which are avirulent and non-persistent in vivo, leads to protection against infection. Immunisation with phosphomannomutase-deficient parasites neither leads to differences in IFN-c, IL-12, IL-4 production nor alters the expression of effector and memory markers, including CD62L, IL-7Ra and IL-2Ra, when compared with unvaccinated controls. Observed protection is due to the ability of vaccinated animals to suppress early IL-10 and IL-13 production and to recruit a higher number of antigen-experienced CD44 hi CD4 1 and CD44 hi CD8 1 T cells into draining LN following infection. Thus, expansion of T-cell numbers and their rapid recruitment to LN upon infection as well as the restriction of IL-13 and IL-10 production leading to high IFN-c/IL-10 ratio play an important role in protection against Leishmania affecting the outcome of the disease in favour of the host.
Clinical and Experimental Immunology, 1999
Peripheral blood mononuclear cells (PBMC) from patients who have recovered from visceral leishmaniasis often respond to Leishmania antigens in vitro by production of both IL-4, IFN-g and IL-10. In order to establish the cellular sources of these cytokines, we activated cells from individuals with a history of visceral leishmaniasis with Leishmania antigen for 6 days in culture, and identi®ed cytokine production at the single-cell level by¯ow cytometry. The cytokines were only found in CD3 cells and among these mainly within the CD4 subset. The percentage of cytokine-producing cells was compared in Leishmania-activated PBMC cultures from the previous patients and from individuals living in a village where leishmaniasis does not occur. The percentage of IL-10-and IFN-g-containing cells was signi®cantly higher in the previous patients than in the controls, indicating that Leishmania-speci®c T cells producing IL-10 and/or IFN-g had been expanded as a result of the infection. The cytokine-producing cells in the previous patients could be divided into three types: (i) cells producing IFN-g only; (ii) cells producing IL-4 only; and (iii) cells producing IFN-g and IL-10 simultaneously. The ®rst and second group of cells can be described as Th1-and Th2-type cells, respectively. The third group could be a regulatory subset of T cells important for maintaining a balance between Th1-and Th2-type cells in these individuals.
Clinical & Experimental Immunology, 2014
An exacerbated type 1 response to leishmanial antigens is the basis of tissue destruction observed in mucosal leishmaniasis (ML). After therapy, a persistent production of high levels of inflammatory cytokines can confer a poor prognosis. Herein we investigated whether the clinical conditions defined during the active phase of ML affect the magnitude of long-term anti-Leishmania immune response. Twenty clinically cured ML cases were studied. Peripheral blood mononuclear cells (PBMC) were cultured with L. braziliensis antigens (Lb-Ag), Toxoplasma gondii antigens (Tg-Ag), concanavalin-A (Con-A) or medium alone, and the lymphocyte proliferative response and cytokine secretion were quantified. Medical records were reviewed for Montenegro skin test (MST) during diagnosis, duration of ML disease or time elapsed after clinical cure. The duration of disease was correlated positively with MST (r = 0·61).
Analysis of T helper cell responses during infection with Leishmania amazonensis
The American Journal of Tropical Medicine and Hygiene, 2002
Most inbred strains of mice are susceptible to Leishmania amazonensis infection and develop progressive cutaneous lesions. However, the role of Th subsets in the disease and the molecular basis of pathogenesis are unclear. To address this issue, we examined the frequency of cytokine-producing CD4 + T cells and the profile of ␣ T cell receptor (TCR) usage in infected BALB/c mice. At different infection stages, CD4 + cells of draining lymph nodes contained comparable frequencies of Th1 and Th2 cells, produced comparable levels of interleukin-4 (IL-4) and interferon-␥ in vitro, and showed no significant bias in ␣TCR usage. However, T cells became highly polarized to a Th2 phenotype (IL-4 + , IL-10 +) within a few cycles of in vitro restimulation. These Th2 cells preferentially expressed V␣2, V4, or V8.1/8.2, and significantly exacerbated disease in cell-transferred mice. Thus, unlike a Th2-dominant phenotype seen in L. major infection, a mixed Th1/Th2 response can be maintained in L. amazonensis-infected mice via an as-yet-unidentified mechanism.
IL10 leads to a higher parasite persistence in a resistant mouse model of Leishmania major infection
Parasitology International, 2002
IL-10 is a cytokine secreted by a wide variety of cell types and has pleiotropic activities, mainly as a modulator of the immune response. In this study, we tested in a direct way the influence of IL-10 expression on Leishmania major infection in resistant mice. We report that C57BLy6 mice treated with a single inoculation of recombinant adenovirus vector-expressing viral IL-10 (Ad-vIL-10), 1 day before parasitic challenge, exhibited a dual effect on footpad swelling, characterized by a decrease on lesion size at the early stage of the infection, followed by a rapid increase of these lesions that attained the complete healing later in infection. The reduction in lesion swelling in vIL-10 treated mice was accompanied by a decrease cellular infiltration of lymphocytes and monocytes at the site of parasite inoculation. Most significantly, vIL-10 administration led to a higher parasite burden in the draining popliteal lymph nodes late during infection, when the complete healing of the lesions was already achieved. RT-PCR analysis showed no important modification of cytokine transcripts in vIL-10 treated mice, early in infection, indicating no changes in mouse phenotype from resistant to susceptible status. Therefore, IL-10 administration influenced the outcome of the disease by modifying the inflammation and local cell recruitment at the site of parasite penetration and by leading to an enhanced residual parasite load in popliteal lymph nodes later in infection. The implication of IL-10 on the host immune status and the establishment and outcome of the infection is discussed. ᮊ
PLoS Pathogens, 2013
In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cellspecific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFNc or IFN-c and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.
Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection
Journal of immunology (Baltimore, Md. : 1950), 1997
Most inbred strains of mice are susceptible to Leishmania amazonensis infection. We have examined the mechanism(s) underlying this generalized susceptibility using mice deficient in T cell development or in the expression of either MHC class I or class II. In contrast to wild-type C57BL/6 (B6) mice that uniformly developed large ulcerating lesions, mice lacking functional CD4+ T cells (due to targeted disruption of genes for either MHC class II trans-activator or I-A beta) showed no signs of lesion development for up to 12 to 14 wk postinfection and contained significantly lower numbers of parasites in lesions. Similarly, both B6 nude and RAG2 -/- mice failed to develop lesions. However, RAG2 -/- mice reconstituted with naive wild-type CD4+ T cells and beta2m -/- mice did develop lesions. Lesions of MHC class II -/- mice contained minimal numbers of CD8+ T cells, a marked reduction of monocytes/macrophages, and evident extracellular parasites. The inability to mount an inflammatory ...