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Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla.
Proc Natl Acad Sci U S A 2019; 116(44):22262-22268PN

Abstract

Interleukin-4 (IL-4) is produced by a unique subset of invariant natural killer T (iNKT) cells (NKT2) in the thymus in the steady state, where it conditions CD8+ T cells to become "memory-like" among other effects. However, the signals that cause NKT2 cells to constitutively produce IL-4 remain poorly defined. Using histocytometry, we observed IL-4-producing NKT2 cells localized to the thymic medulla, suggesting that medullary signals might instruct NKT2 cells to produce IL-4. Moreover, NKT2 cells receive and require T cell receptor (TCR) stimulation for continuous IL-4 production in the steady state, since NKT2 cells lost IL-4 production when intrathymically transferred into CD1d-deficient recipients. In bone marrow chimeric recipients, only hematopoietic, not stromal, antigen-presenting cells (APCs), provided such stimulation. Furthermore, using different Cre-recombinase transgenic mouse strains to specifically target CD1d deficiency to various APCs, together with the use of diphtheria toxin receptor (DTR) transgenic mouse strains to deplete various APCs, we found that macrophages were the predominant cell to stimulate NKT2 IL-4 production. Thus, NKT2 cells appear to encounter and require different activating ligands for selection in the cortex and activation in the medulla.

Authors+Show Affiliations

Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.Center for Immunology, University of Minnesota, Minneapolis, MN 55455; hogqu001@umn.edu. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31611396

Citation

Wang, Haiguang, et al. "Myeloid Cells Activate iNKT Cells to Produce IL-4 in the Thymic Medulla." Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 44, 2019, pp. 22262-22268.
Wang H, Breed ER, Lee YJ, et al. Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. Proc Natl Acad Sci USA. 2019;116(44):22262-22268.
Wang, H., Breed, E. R., Lee, Y. J., Qian, L. J., Jameson, S. C., & Hogquist, K. A. (2019). Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. Proceedings of the National Academy of Sciences of the United States of America, 116(44), pp. 22262-22268. doi:10.1073/pnas.1910412116.
Wang H, et al. Myeloid Cells Activate iNKT Cells to Produce IL-4 in the Thymic Medulla. Proc Natl Acad Sci USA. 2019 Oct 29;116(44):22262-22268. PubMed PMID: 31611396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. AU - Wang,Haiguang, AU - Breed,Elise R, AU - Lee,You Jeong, AU - Qian,Lily J, AU - Jameson,Stephen C, AU - Hogquist,Kristin A, Y1 - 2019/10/14/ PY - 2020/04/14/pmc-release PY - 2019/10/16/pubmed PY - 2019/10/16/medline PY - 2019/10/16/entrez KW - IL-4 KW - NKT2 KW - iNKT cells KW - macrophage KW - thymus SP - 22262 EP - 22268 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 116 IS - 44 N2 - Interleukin-4 (IL-4) is produced by a unique subset of invariant natural killer T (iNKT) cells (NKT2) in the thymus in the steady state, where it conditions CD8+ T cells to become "memory-like" among other effects. However, the signals that cause NKT2 cells to constitutively produce IL-4 remain poorly defined. Using histocytometry, we observed IL-4-producing NKT2 cells localized to the thymic medulla, suggesting that medullary signals might instruct NKT2 cells to produce IL-4. Moreover, NKT2 cells receive and require T cell receptor (TCR) stimulation for continuous IL-4 production in the steady state, since NKT2 cells lost IL-4 production when intrathymically transferred into CD1d-deficient recipients. In bone marrow chimeric recipients, only hematopoietic, not stromal, antigen-presenting cells (APCs), provided such stimulation. Furthermore, using different Cre-recombinase transgenic mouse strains to specifically target CD1d deficiency to various APCs, together with the use of diphtheria toxin receptor (DTR) transgenic mouse strains to deplete various APCs, we found that macrophages were the predominant cell to stimulate NKT2 IL-4 production. Thus, NKT2 cells appear to encounter and require different activating ligands for selection in the cortex and activation in the medulla. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/31611396/Myeloid_cells_activate_iNKT_cells_to_produce_IL-4_in_the_thymic_medulla L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=31611396 DB - PRIME DP - Unbound Medicine ER -