title: CD275-Independent IL-17-Producing T Follicular Helper-like Cells in Lymphopenic Autoimmune-Prone Mice.
abstract: T cells undergo homeostatic expansion and acquire an activated phenotype in lymphopenic microenvironments. Restoration of normal lymphocyte numbers typically re-establishes normal homeostasis, and proinflammatory cytokine production returns to baseline. Mice deficient in guanine nucleotide exchange factor RasGRP1 exhibit dysregulated homeostatic expansion, which manifests as lymphoproliferative disease with autoantibody production. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development, as well as during germinal center responses, suggesting that T cell-independent and T cell-dependent mechanisms are responsible. Examination of whether a particular T cell subset is involved in the breach of B cell tolerance revealed increased Th17 cells in Rasgrp1-deficient mice relative to control mice. Rasgrp1-deficient mice lacking IL-17R had fewer germinal centers, and germinal centers that formed contained fewer autoreactive B cells, suggesting that IL-17 signaling is required for a break in B cell tolerance in germinal centers. Interestingly, a fraction of Th17 cells from Rasgrp1-deficient mice were CXCR5(+) and upregulated levels of CD278 coordinate with their appearance in germinal centers, all attributes of T follicular helper cells (Tfh17). To determine whether CD278-CD275 interactions were required for the development of Tfh17 cells and for autoantibody, Rasgrp1-deficient mice were crossed with CD275-deficient mice. Surprisingly, mice deficient in RasGRP1 and CD275 formed Tfh17 cells and germinal centers and produced similar titers of autoantibodies as mice deficient in only RasGRP1. Therefore, these studies suggest that requirements for Tfh cell development change in lymphopenia-associated autoimmune settings.
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Buhlmann
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688; and.
authors.forename: Xiaogan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688; and.
authors.forename: Amber
authors.initials: A
authors.lastname: Bartlett
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688; and rbarrington@southalabama.edu.
authors.forename: Robert A
authors.identifier: 0000-0001-5713-5369
authors.initials: RA
authors.lastname: Barrington
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency; D006706:Homeostasis; D007108:Immune Tolerance / Q000235:genetics; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000172:deficiency / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D054380:Receptors, CXCR5 / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000172:deficiency; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D001323:Autoantibodies; C513179:CXCR5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C491673:Il17ra protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; C112278:Rasgrp1 protein, mouse; D054380:Receptors, CXCR5; D053722:Receptors, Interleukin-17