title: SerpinB1 regulates homeostatic expansion of IL-17+ γδ and CD4+ Th17 cells.
abstract: SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a(-/-) mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A(+) γδ and CD4(+) Th17 cells are already expanded in the lungs of serpinb1a(-/-) mice at steady-state. Both γδ and αβ(+) CD4(+) CCR6(+) T cells isolated from the lungs of naive serpinb1a(-/-) mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (RORγt)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in γδ T cells. In addition to the lung, IL-17A(+) γδ and CD4(+) Th17 cells were increased in the spleen of naive serpinb1a(-/-) mice, despite normal αβ and γδ T cell development in the thymus. Within the γδ T cell compartment, loss of serpinb1a prompted selective expansion of Vγ4(+) and Vγ6/Vδ1(+) cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A(+) γδ and CD4(+) Th17 cell subsets vis-à-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype.
authors.affiliation: 5.3 Blackfan Circle, Boston, MA 02115, USA. eileen.remold-odonnell@childrens.harvard.edu.
authors.forename: Picheng
authors.initials: P
authors.lastname: Zhao
authors.forename: Lifei
authors.initials: L
authors.lastname: Hou
authors.forename: Kalamo
authors.initials: K
authors.lastname: Farley
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009976:Orthomyxoviridae Infections / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D015843:Serpins / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016692:Receptors, Antigen, T-Cell, gamma-delta; C522950:Serpinb1a protein, mouse; D015843:Serpins
keywords: cell proliferation; cytokine regulation; inflammation; lymphocytes; population size