title: Signaling through the T1/ST2 molecule is not necessary for Th2 differentiation but is important for the regulation of type 1 responses in nonhealing Leishmania major infection.
abstract: T1/ST2 is a stable cell surface marker selectively expressed on type 2 T helper (Th2) effector cells. Since nonhealing Leishmania major infections in susceptible BALB/c mice have been ascribed to a polarized Th2 response, we used an anti-T1/ST2 monoclonal antibody (MAb) or a T1-Fc fusion protein to investigate the role of CD4+ T1/ST2(+) Th2 cells in experimental leishmaniasis. We show that interfering with T1/ST2 signaling had no effect on lesion development or parasite replication; however, it induced a significantly higher type 1 response and an enhanced capacity of CD4+ T cells to respond to interleukin 12 (IL-12). Surprisingly, even in the presence of an elevated Th1 response, the production of antigen-specific type 2 cytokines was not altered in the group of mice treated with the anti-T1/ST2 MAb or the T1-Fc fusion protein. To characterize further this Th2 response, we assessed the cytokine profile of CD4+ T cells and found that interfering with T1/ST2 signaling did not alter the cytokine profile of CD4+ T1/ST2(+) T cells. These results show that T1/ST2 signaling is not necessary for the differentiation of naive CD4+ T cells into antigen-specific CD4+ T1/ST2(+) Th2 cells. In addition to CD4+ T1/ST2(+) T cells, we detected another subpopulation of CD4+ Th2 cells, negative for the expression of T1/ST2, that could differentiate in vivo in response to L. major infection. Taken together, our results suggest that CD4+ T1/ST2(+) Th2 cells but not CD4+ T1/ST2(-) Th2 cells can downregulate the Th1 response during the course of a nonhealing L. major infection through a mechanism that is independent of IL-4 or IL-10.
authors.affiliation: Division of Investigative Science, Department of Immunology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Norfolk Place, London W2 1PG, UK.
authors.forename: P
authors.initials: P
authors.lastname: Kropf
authors.forename: S
authors.initials: S
authors.lastname: Herath
authors.forename: R
authors.initials: R
authors.lastname: Klemenz
authors.forename: I
authors.initials: I
authors.lastname: Müller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018320:Leishmania major / Q000276:immunology* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C486189:Il1rl1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins