title: Transforming growth factor-β1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection.
abstract: As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to T cell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing α-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-β1 (TGF-β1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-β1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-β1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections.
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bhaskaran
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: C
authors.initials: C
authors.lastname: Quigley
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Weinberg
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: D
authors.initials: D
authors.lastname: Popkin
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pandiyan
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D002177:Candidiasis / Q000276:immunology*; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009960:Oropharynx / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D053181:Caspase 8