title: Opposing effects of CTLA4 insufficiency on regulatory versus conventional T cells in autoimmunity converge on effector memory in target tissue.
abstract: Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (T(reg)) but also required for intrinsic control of conventional T (T(conv)) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg function both in vivo and in vitro. It led to an increase in T(reg) memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the T(conv) compartment. The CD4(+) conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-γ. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both T(conv) and T(reg) lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
authors.forename: Priyadharshini
authors.initials: P
authors.lastname: Devarajan
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
authors.forename: Jason
authors.initials: J
authors.lastname: Miska
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
authors.forename: Jen Bon
authors.initials: JB
authors.lastname: Lui
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and.
authors.forename: Dominika
authors.initials: D
authors.lastname: Swieboda
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136 zchen@med.miami.edu.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D006183:H-2 Antigens / Q000235:genetics; D007150:Immunohistochemistry; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D060908:CTLA-4 Antigen; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D007371:Interferon-gamma