Valérie Julia

Resistance to Leishmania major Induced by Tolerance to a Single Antigen

In mice, susceptibility to Leishmania major is associated with the early expansion of T helper 2 cells (TH2) cells, but nothing is known of the specificity of these cells. A previously identified antigen, Leishmania homolog of receptors for activated C kinase (LACK), was found to be the focus of this initial response. Mice made tolerant to LACK by the transgenic expression of the antigen in the thymus exhibited both a diminished TH2 response and a healing phenotype. Thus, T cells that are activated early and are reactive to a single antigen play a pivotal role in directing the immune response to the entire parasite.

A Restricted Subset of Dendritic Cells Captures Airborne Antigens and Remains Able to Activate Specific T Cells Long after Antigen Exposure

Mice sensitized for a Th2 response to Leishmania LACK antigen developed allergic airway inflammation upon exposure to LACK aerosol. Using multimers of I-A(d) molecules bound to a LACK peptide as probes, we tracked the migration of LACK-specific Th2 cells to the airways. Elevated numbers of LACK-specific Th2 cells remained in the airways for 5 weeks after the last aerosol. Substantial numbers of DC presenting LACK peptides were found in the airways, but not in other compartments, for up to 8 weeks after antigen exposure. These LACK-presenting airway DC expressed CD11c and CD11b as well as high levels of surface molecules involved in uptake and costimulation. Taken together, our results may explain the chronic Th2 airway inflammation characteristic of allergic asthma.

Selective Activation and Expansion of High-Affinity CD4+ T Cells in Resistant Mice upon Infection with Leishmania major

Using multimers of MHC class II molecules linked to a peptide derived from the Leishmania LACK antigen, we have compared the fate of parasite-specific CD4+ T cells in resistant and susceptible mice transgenic for the beta chain of a LACK-specific TCR. Activated T cells were readily detected in the draining lymph nodes of infected animals. Although the kinetics of activation and expansion were similar in both strains, T cells from susceptible and resistant mice expressed low- and high-affinity TCR, respectively. As T cells from resistant mice produced more IFN-gamma and less IL-4 than those from susceptible animals, our results suggest that differences in TCR usage between MHC-matched animals may influence the development of the antiparasite immune response.

CD4+ T Cell Polarization in Mice Is Modulated by Strain-specific Major Histocompatibility Complex–independent Differences within Dendritic Cells

Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b+ dendritic cells (DCs) prime parasite-specific CD4+ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major–infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4+ T cells. Thus, strain-specific differences within CD11b+ DCs influence the ability of inbred mice to mount polarized CD4+ T cell responses.

Priming by Microbial Antigens from the Intestinal Flora Determines the Ability of CD4+ T Cells to Rapidly Secrete IL-4 in BALB/c Mice Infected with Leishmania major

Infection of BALB/c mice with Leishmania major results in the rapid accumulation of IL-4 transcripts within CD4+ T cells that react to the parasite Leishmania homologue of mammalian RACK1 (LACK) Ag. Because memory/effector cells secrete IL-4 more rapidly than naive cells, we sought to analyze the phenotype of these lymphocytes before infection. Indeed, a fraction of LACK-specific CD4+ T cells expressed a typical CD62 ligandlowCD44highCD45RBlow phenotype in uninfected mice. LACK-specific T cells were primed in gut-associated lymphoid tissues by cross-reactive microbial Ags as demonstrated by their reactivity with bacterial extracts and by the ability of APCs from the mesenteric LN of BALB/c mice to induce their proliferation. Also, mice in which the digestive tract has been decontaminated exhibited a reduced proportion of LACK-specific T cells expressing a memory/effector phenotype and did not exhibit the early accumulation of IL-4 transcripts induced by L. major. Thus, LACK-specific T cells represent a subset of CD4+ T cells which have acquired the ability to rapidly secrete IL-4 as the result of their priming by cross-reactive microbial Ags. Tracking the fate of these cells may provide information about the regulation of cell-mediated immune responses to gut Ags in physiological and pathological situations.

Selective tolerization of Th1‐like cells after nasal administration of a cholera toxoid‐LACK conjugate

Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T cells responding to a single antigen, LACK (Leishmaniahomologue of receptors for activated C kinase), drive the differentiation of other responding T cells to the Th2 phenotype and so allow lesion development to occur. Transgenic mice expressing LACK in the thymus are tolerant to LACK and thus resolve infection with L. major. The oral administration of soluble protein to mice has been shown to result in the peripheral tolerance of antigen‐specific CD4+ T cells. We therefore sought to tolerize LACK reactive T cells in non‐transgenic BALB/c mice in order to determine the effectiveness of this tolerization approach as an alternative to standard vaccination protocols againist L. majorinfection. Surprisingly, oral or nasal administration of up to 8 mg of recombinant LACK did not affect the outcome of infection. We therefore conjugated LACK to cholera toxin β subunit (CTB‐LACK) which has previously been shown to improve the effectiveness of oral tolerance to conjugated antigens. Nasal administration of as little as 12 μg of CTB‐LACK effectively diminished the capacity of mice to mount a subsequent proliferative response to LACK and further delayed the onset of lesion development in infected mice. However, pretreatment with CTB‐LACK did not prevent the eventual onset and progression of disease in these mice. An examination of cytokine responsiveness to LACK after tolerization with CTB‐LACK revealed that while the Th1 response to LACK was suppressed, Th2 cytokine production was unaffected. Similar experiments using an ovalbumin‐CTB conjugate suggested that this selective tolerance of Th1 cells was not specific to the LACK protein but may be an effect common to CTB‐conjugated proteins.

CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin

Fractalkine interactions with its receptor, CX3CR1, regulate CD4+ T cell retention in atopic dermatitis and offer a potential therapeutic target in allergic disease.

Topical ivermectin improves allergic skin inflammation

Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti‐inflammatory properties.

The “one airway, one disease” concept in light of Th2 inflammation

In line with the pathophysiological continuum described between nose and bronchus in allergic respiratory diseases, we assessed whether nasal epithelium could mirror the Type 2 T-helper cell (Th2) status of bronchial epithelium. Nasal and bronchial cells were collected by brushing from healthy controls (C, n=13), patients with allergic rhinitis and asthma (AR, n=12), and patients with isolated allergic rhinitis (R, n=14). Cellular composition was assessed by flow cytometry, gene expression was analysed by RNA sequencing and Th2, Type 17 T-helper cell (Th17) and interferon (IFN) signatures were derived from the literature. Infiltration by polymorphonuclear neutrophils (PMN) in the nose excluded 30% of the initial cohort. All bronchial samples from the AR group were Th2-high. The gene expression profile of nasal samples from the AR group correctly predicted the paired bronchial sample Th2 status in 71% of cases. Nevertheless, nasal cells did not appear to be a reliable surrogate for the Th2 response, in particular due to a more robust influence of the IFN response in 14 out of 26 nasal samples. The Th2 scores in the nose and bronchi correlated with mast cell count (both p<0.001) and number of sensitisations (p=0.006 and 0.002), while the Th17 scores correlated with PMN count (p=0.006 and 0.003). The large variability in nasal cell composition and type of inflammation restricts its use as a surrogate for assessing bronchial Th2 inflammation in AR patients. Nasal epithelial cells are not good surrogates for bronchial epithelial cells in the evaluation of Th2 inflammation http://ow.ly/if5u30ltyx5