The immune system strikes a remarkably tight balance between controlling infections while still limiting immunity to self tissues (‘autoimmunity’). A case in point is T cell derived cytokines: while critical for protecting against infectious disease, they are also central to driving pathology in most autoimmune conditions. Consequently, ‘biologic’ drugs that neutralize cytokines have become mainstays of treating autoimmune diseases.
The Gaffen lab takes a basic science approach to understand the molecular and cellular mechanisms that underline cytokine-mediated inflammation, whether for good (prevent infections) or bad (promote autoimmune pathology). Our main focus is IL-17, which is produced mainly by T cells and other lymphocytes.
IL-17 SIGNAL TRANSDUCTION
IL-17 acts mainly on stromal and epithelial cells, and hence links the immune system with inflamed tissues. IL-17 and its receptor are unique in structure and sequence from other known cytokine families, and the Gaffen lab was among the first to study the molecular signaling mechanisms induced by this novel family of cytokines. Efforts to understand this pathway in depth are a major focus of the lab.
IL-17 IN INFECTIONS
Dr. Gaffen’s group was the first to demonstrate that IL-17 is critical for immunity to mucosal infections with a common commensal fungus, Candida albicans. Although normally not a problem in healthy individuals, C. albicans is the causative agent of oral and vaginal thrush and also of a serious hospital-acquired form of candidiasis that can be associated with >50% mortality.
IL-17 IN AUTOIMMUNITY
Antibodies that neutralize IL-17 were approved in 2016 to treat psoriasis and are under evaluation for other autoimmune or immunopathological diseases. Dr. Gaffen’s lab aims to understand both the physiological impact of cytokine blockade, as well as the ways in which understanding signaling might be exploited for therapeutic benefit.
Gaffen, Principal Investigator
|R37-DE022550 – “Host and fungal regulation of Type 17 immunity to oral candidiasis”, 2017-2022|
|R01- AI147383 “Molecular mechanisms of IL-17-dependent autoimmune signaling” 2019-2024|
|Gerald P. Rodnan Endowed Chair|
|R01-CA214865 (PI Allan Tsung) “Surgery triggered immune response and liver metastases” 2017-22|
|T32-AI089443 (PI Mark Schlomchik) “Autoimmunity and Immunopathology Training Program”|
R01-AI142354 (PI Partha Biswas) “Mechanisms of neutrophil dysfunction in antifungal immunity” 2019-24
R21-AI159058 (PI Partha Biswas) “Mechanisms of renal protection against disseminated candidiasis” 2021-23
Amatya N, Garg AV, Gaffen SL. IL-17 signaling: The Yin and the Yang. Trends Immunol. 2017; 38:310-322. https://www.ncbi.nlm.nih.gov/pubmed/28254169
Conti HR, Gaffen SL. IL-17 and Candida albicans infections. J Immunol, 2015; 195:780-788. https://www.ncbi.nlm.nih.gov/pubmed/26188072
McGeachy MJ, Cua D and Gaffen SL, The IL-17 Family of Cytokines in Health and Disease. Immunity 2019; 50:892. https://www.cell.com/action/showPdf?pii=S1074-7613%2819%2930138-4
Li X., Bechara R, Zhao J, McGeachy MJ, Gaffen SL. IL-17 receptor-based signaling and implications for disease. Nature Immunology 2019; 20:1594. https://www.nature.com/articles/s41590-019-0514-y
Gaffen SL, Moutsopoulos N. Regulation of Host-Microbe Interactions at Oral Mucosal Barriers by Type 17 Immunity. Science Immunology 2020; 5:eaau4594. https://immunology.sciencemag.org/content/5/43/eaau4594
Fungal Immunity and IL-17/TH17 Cells
Zhou C, Monin L, Gordon R, Aggor FEY, Bechara R, Edwards T, Kaplan DH, Gingras S, Gaffen SL. An IL-17F.S65L knock-in mouse reveals similarities and differences in IL-17F function in oral candidiasis: A new tool to understand IL-17F. J Immunol, 2020; 205:720. https://www.jimmunol.org/content/205/3/720.long. ***Note, mice will be available from MMRRC some time in 2021
Aggor FEY, Break TJ, Trevejo-Nunez G, Whibley N, Coleman BM, Bailey RD, Kaplan DH, Naglik JR, Shan W, Shetty AC, McCracken C, Durum SK, Biswas PS, Bruno VM, Kolls JK, Lionakis MS, Gaffen SL. Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis. Science Immunology, 2020; 5:eaba0570. https://immunology.sciencemag.org/content/5/48/eaba0570.long
Conti HR, Bruno VM, Childs EC, Daugherty S, Hunter JP, Mengesha BG, Saevig DL, Hendricks MR, Coleman BM, Brane L, Solis N, Cruz JA, Verma AH, Garg AV, Hise AG, Richardson JP, Naglik JR, Filler SG, Kolls JK, Sinha S, Gaffen SL. IL-17RA signaling in oral epithelium is critical for protection against oropharyngeal candidiasis. Cell Host & Microbe, 2016; 20:606-617.
https://www.ncbi.nlm.nih.gov/pubmed/27923704 *** Note, mice available from The Jackson Laboratory https://www.jax.org/strain/034382
Verma AH, Richardson JP, Moyes DL, Ho J, Huppler AR, Ramani K, Coleman BM, Kane LP, Biswas PS, Hube B, Naglik JR, Gaffen SL. Oral epithelial cells orchestrate innate Type 17 responses to Candida albicans through the virulence factor Candidalysin. Science Immunology, 2017; 2:eaam8834.
Verma AH*, Zafar H*, Ponde NO, Hepworth OW, Sihra D, Aggor FEY, Ainsough JS, Ho J, Richardson JP, Coleman BM, Hube B, Stacey M, McGeachy MJ, Naglik JP, Gaffen SL*, Moyes DL*. IL-36 and IL-1/IL-17 drive immunity to oral candidiasis via parallel mechanisms. J Immunol, 2018; 201:627-634.
Conti HR, Peterson AC, Huppler AR, Brane L, Hernández-Santos N, Whibley N, Garg AV, Simpson-Abelson MR, Gibson G, Mamo AJ, Osborne LC, Bishu S, Ghilardi N, Siebenlist U, Watkins SC, Artis D, McGeachy MJ, Gaffen SL. Oral-resident ‘natural’ Th17 cells and gd-T cells control opportunistic Candida albicans infections. J Exp Med, 2014; 211:2075-2084.
Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med, 2009; 206:299-311
Autoimmunity and Anti-cytokine Drugs
Shen F, Verma AH, Volk A, Jones B, Coleman BM, Loza M, Malaviya R, Elloso M, Gaffen SL*, Ort T*. Combined blockade of TNFα and IL-17A alleviates progression of collagen-induced arthritis without causing serious infections in mice. 2019; J Immunol, 202:2017-2026.
Monin L, Gudjonsson JE, Childs EE, Amatya N, Xing X, Verma AV, Coleman BM, Killeen M, Mathers A, Ward NL, Gaffen SL. MCPIP1/Regnase-1 restricts IL-17A- and IL-17C-dependent skin inflammation. J Immunol, 2017; 198:767-775.
Whibley N, Tritto E, Traggiai E, Kolbinger F, Moulin P, Brees D, Coleman BM, Mamo AJ, Garg AV, Jaycox J, Siebenlist U, Kammüller M, Gaffen SL. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral candidiasis. J Leuk Biol, 2016; 99:1153-1164.
Whibley N, Gaffen SL. Gut-Busters: IL-17 Ain’t Afraid of no IL-23. Commentary on Maxwell et al. and Lee et al., Immunity, 2015; 43:620-621.
Garg A, Ahmed M, Vallejo A, Ma A, Gaffen SL*. The deubiquitinase A20 mediates feedback inhibition of Interleukin-17 receptor signaling. Science Signaling, 2013; 6:ra44.
Goswami J, Hernández-Santos N, Zuniga LA, Gaffen SL*. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur J Immunol, 2009; 39:2831-2839.
Mechanisms of IL-17 Receptor Signaling
Bechara R, Amatya N, Bailey RD, Li Y, Aggor FEY, Li D, Jawale C, Coleman BM, Dai N, Gokhale NS, Taylor TC, Horner SM, Poholek AC, Bansal A, Biswas PS, Gaffen SL. The m6A reader IMP2 directs autoimmune inflammatoin through an IL-17- and TNFalpha-dependent C/EBP transcription factor axis. Science Immunology, 2021; 6:eabd1287. http://immunology.sciencemag.org/cgi/content/full/6/61/eabd1287?ijkey=Ar2nw4ClbBkV2&keytype=ref&siteid=immunology
Amatya N, Childs EE, Cruz JA, Aggor FEY, Garg AV, Berman AJ, Gudjonsson JE, Atasoy U, Gaffen SL*. IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA-binding protein Arid5a. Science Signaling, 2018; 11:eaat4617.
Garg AV, Amatya N, Chen K, Cruz JA, Grover P, Whibley N, Conti HR, Mir GH, Sirakova T, Childs EC, Smithgall TE, Biswas PS, Kolls JK, McGeachy MJ, Kollatukudy PE, Gaffen SL. MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation. Immunity, 2015; 43:475-487.
Ho AW, Shen F, Conti HR, Patel N, Childs EE, Peterson AC, Hernández-Santos N, Kolls JK, Kane LP, Ouyang W, Gaffen SL. IL-17RC is required for immune signaling via an extended SEFIR domain in the cytoplasmic tail. J Immunol, 2010; 185:1063-70.
Shen F, Li N, Gade P, Kalvakolanu D, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL. IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Science Signaling, 2009; 2:ra8.
Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci, USA, 2007; 104:7506-7511.
Other Articles of Interest
Shapiro VS, Kovats S, Parent MA, Gaffen SL, Hedrick CC, Jain P, Denzin LK, Raghavan M, Stephens R. Update on gender equity in immunology, 2001 to 2016. J. Immunol., 2016; 197:3751-3753.
Gaffen SL. Pillars of Immunology: Life Before Seventeen: Cloning of the IL-17 Receptor. J Immunol, 2011; 187:4389-4391 (commentary on “Pillars” article: Yao et al., Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor, Immunity, 3:811-21, 1995).