ABSTRACT
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
Subject(s)
CD8-Positive T-Lymphocytes , Disease Models, Animal , Lacrimal Apparatus , Mice, Inbred NOD , Sjogren's Syndrome , Animals , Sjogren's Syndrome/immunology , Mice , CD8-Positive T-Lymphocytes/immunology , Lacrimal Apparatus/immunology , Lacrimal Apparatus/pathology , Interleukins/immunology , Interleukins/metabolism , CD4-Positive T-Lymphocytes/immunology , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Female , Signal Transduction/immunology , Receptors, Interleukin/immunology , Interleukin-27/metabolism , Interleukin-27/immunology , Inducible T-Cell Co-Stimulator Protein/immunology , Inducible T-Cell Co-Stimulator Protein/metabolism , Apyrase/immunology , Apyrase/metabolismABSTRACT
Glycerol Monolaurate (GML) is a naturally occurring fatty acid monoester with antimicrobial properties. Francisella tularensis is an agent of bioterrorism known for its unique lipopolysaccharide structure and low immunogenicity. Here we assessed whether exogenous GML would inhibit the growth of Francisella novicida . GML potently impeded Francisella growth and survival in vitro . To appraise the metabolic response to infection, we used GC-MS to survey the metabolome, and surprisingly, observed intracellular GML production following Francisella infection. Notably, the ubiquitin-like protein ISG15 was necessary for increased GML levels induced by bacterial infection, and enhanced ISG15 conjugation correlated with GML levels following serum starvation.
