A Leishmania major Response Locus Identified by Interval-specific Congenic Mapping of a T Helper Type 2 Cell Bias-controlling Quantitative Trait Locus (original) (raw)
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Identification of Two Distinct Subpopulations of Leishmania major-Specific T Helper 2 Cells
Infection and Immunity, 2002
It is widely accepted that a strong Th2 response is responsible for nonhealing Leishmania major infections in BALB/c mice. This Th2 response has been thoroughly documented by measuring the levels of Th2 cytokines produced by CD4 ؉ T cells present in the lymphoid organs by enzyme-linked immunosorbent assay and PCR. However, the cytokine profile of L. major-specific Th2 cells has never been determined. In this study, we used the recently described Th2 marker T1/ST2 to characterize Th2 cells during the course of nonhealing L. major infection. We analyzed the intracellular cytokine profile of CD4 ؉ T1/ST2 ؉ T cells and showed that they clearly displayed a Th2 phenotype, as they expressed interleukin 4 (IL-4), IL-10, and IL-5. In addition, we detected another population of Th2 cells among the CD4 ؉ T1/ST2 ؊ T cells that expressed IL-4 and IL-10 but excluded IL-5. In summary, we show here that two type 2 subpopulations are present in the lymphoid organs of L. major-infected BALB/c mice; Th2 cells from both subsets expressed IL-4 and IL-10, but they could be distinguished by their expression of IL-5 and T1/ST2.
2000
Susceptibility as opposed to resistance of mouse strains (eg, BALB/c vs C57BL/6) to Leishmania major has been attributed to a defective Th1 and a predominant Th2-response, resulting in increased IL-4 and IgE production, and decreased interferon gamma (IFN␥) production, macrophage activation and elimination of parasites. Here we report dissection of genetic and functional aspects of susceptibility to leishmaniasis using two contrasting inbred strains BALB/cHeA (susceptible) and STS/A (resistant) and a resistant Recombinant Congenic (RC) Strain, CcS-5/Dem, which carries a random set of 12.5% of genes from the strain STS and 87.5% genes from the susceptible strain BALB/c. Linkage analysis of F 2 hybrids between the resistant RC strain CcS-5 and the susceptible strain BALB/c revealed five loci affecting the response to the infection, each apparently associated with a different combination of pathological symptoms and immunological reactions. The correlation between Th2-type immune reactions and the disease in the F 2 mice was either absent, or it was limited to mice with specific genotypes at loci on chromosomes 10 and 17. This suggests that the resistance vs susceptibility is influenced by mechanisms additional to the postulated antagonistic effects of Th1 and Th2 responses, and that the host's genotype affects the development of leishmaniasis in a complex way. Genes and Immunity (2000) 1, 200-206.
Cell biology and immunology of Leishmania
Immunological Reviews, 2011
More than 20 years ago, immunologists discovered that resistance and susceptibility to experimental infection with the intracellular protozoan Leishmania major was associated with the development of T-helper 1 (Th1)-and Th2-dominated immune responses, respectively. This infectious disease model was later used to identify and assess the role of key factors, such as interleukin-12 (IL-12) and IL-4, in Th1 and Th2 maturation. While infection by Leishmania remains a popular model for immunologists who wish to assess the role of their favorite molecule in T-cell differentiation, other investigators have tried to better understand how Leishmania interact with its insect and mammalian hosts. In this review, we discuss some of these new data with an emphasis on the early events that shape the immune response to Leishmania and on the immune evasion mechanisms that allow this parasite to avoid the development of sterilizing immunity and to secure its transmission to a new host.
Susceptibility to Infectious Diseases: Leishmania as a Paradigm
The Journal of Infectious Diseases, 1999
The diverse response of individuals within populations to infectious pathogens remains poorly understood, although genetic determinants undoubtedly contribute in substantial ways to the outcome of infection. In a mouse model of infection with the intramacrophage protozoan Leishmania major, susceptibility correlates both with aberrant helper T cell differentiation biased towards the production of interleukin 4 and with the presence of an endogenous CD4 T cell repertoire that recognizes an immunodominant parasite antigen with high frequency. In the setting of the particular ecological niche occupied by Leishmania, this combination of otherwise unrelated factors synergizes to result in exquisite susceptibility to this single pathogen, without seemingly compromising host defenses against other agents. Similar paradigms could underlie susceptibility to other pathogenic organisms.
Cd4+ T cell response to leishmania spp. in non-infected individuals
Human Immunology, 2000
T cell mediated immunity is known to play a central role in the host response to control intra-cellular pathogens. This work demonstrates the presence of specific CD4(+) T cells to Leishmania spp. antigens in peripheral mononuclear cells of naïve individuals (normal volunteers from non-endemic regions). The responder population was expanded by generation of antigen-specific T cell lines, which were produced by repeated stimulation with fixed promastigotes and autologous irradiated PBMC as antigen presenting cells. The leishmania-T cell lines were shown to proliferate in response to different species of the parasite (L. amazonensis, L. braziliensis, and L. donovani), but not to other recall antigens such as Candida albicans or tetanus toxoid. A preferential expansion of IFNgamma and IL-2 producing Th1-like T cells was observed. The leishmania-reactive cells were distributed between CD4(+) CD45RA(+) ("naïve") and CD4(+) CD45R0(+) ("memory") populations. Although limiting dilution analysis showed a precursor frequency 3 times lower within the naïve compartment, similar numbers of T cell lines were derived from both purified subpopulations. This study using leishmania-specific CD4(+) T cell lines produced from normal individuals should provide information on cellular immune responses that are triggered by the parasite and how infection impacts the naïve T cell repertoire.
Genes and Immunity, 2004
Severity of disease caused by Leishmania major depends on the genetics of the host. Early induction of T helper cell type 1 (Th1)-type responses in resistant C57BL/6 mice and T helper cell type 2 (Th2) in susceptible BALB/c mice is thought to determine cure or disease respectively. We have mapped three loci that confer susceptibility or resistance upon congenic mice on the C57BL/6 or BALB/c backgrounds. Here we examine the histopathology and production of interleukin 4 (IL-4) and interferon gamma (IFN-g) in the skin and draining lymph nodes in the congenic and parental mice. We show an evolving granuloma with a staged infiltration of inflammatory cells, but no difference between the groups. As an indication of an earlypolarised Th1/Th2 response we measured IFN-g and IL-4 in the lymph nodes and found no difference between any of the mice during the first 48 h. During infection, the level of IL-4 correlated with the lesion size, indicating that IL-4 reflects the disease severity rather than controls it. Considering this effect, B6.C(lmr1,lmr2) mice had similar cytokine levels to the parental C57BL/ 6 mice despite increased susceptibility and C.B6(lmr1,lmr2) were similar to BALB/c despite increased resistance. We conclude that the lmr loci affect disease severity by a mechanism independent of conventional helper T-cell responses.
ANALYSIS OF T HELPER CELL RESPONSES DURING INFECTION WITH LEISHMANIA AMAZONENSIS
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
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 ...
Role of host genetics and cytokines in Leishmania infection
Cytokine, 2021
Cytokines and chemokines are important regulators of innate and specific responses in leishmaniasis, a disease that currently affects 12 million people. We overviewed the current information about influences of genetically engineered mouse models of cytokine and chemokine on leishmaniasis. We found that genetic background of the host, parasite species and sub-strain, as well as experimental design often modify effects of genetically engineered cytokine genes. Next we analyzed genes and QTLs (quantitative trait loci) that control response to Leishmania species in mouse in order to establish relationship between genetic control of cytokine expression and organ pathology. These studies revealed a network-like complexity of the combined effects of the multiple functionally diverse QTLs and their individual specificity. Genetic control of organ pathology and systemic immune response overlap only partially. Some QTLs control both organ pathology and systemic immune response, but the effects of genes and loci with the strongest impact on disease are cytokine-independent, whereas several loci modify cytokines levels in serum without influencing organ pathology. Understanding this genetic control might be important in development of vaccines designed to stimulate certain cytokine spectrum.