Research & Publications

General Background

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.


Photo by Bernie Hube 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.


Current Funding

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
R21 AI145242 “Regulation of IL-17 signaling by RNA binding proteins in autoimmune pathology” (Partha Biswas, MPI) 2019-2021
Rheumatology Research Foundation Innovative Research Award (with Dr. Partha Biswas) “Regulation of renal IL-17 signaling in antibody-mediated kidney disease” (2019-21)

Gaffen, Co-Investigator

R01-CA214865 (PI Allan Tsung) “Surgery triggered immune response and liver metastases” 2017-22
T32-AI089443 (PI Mark Schlomchik) “Autoimmunity and Immunopathology Training Program”

Selected Publications

Review Articles

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.
https://www.ncbi.nlm.nih.gov/pubmed/29101209
https://www.ncbi.nlm.nih.gov/pubmed/29101210

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.
https://www.ncbi.nlm.nih.gov/pubmed/29891557
http://www.jimmunol.org/content/201/2/323

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.
https://www.ncbi.nlm.nih.gov/pubmed/25200028

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
https://www.ncbi.nlm.nih.gov/pubmed/19204111
https://www.ncbi.nlm.nih.gov/pubmed/19204107

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.
https://www.ncbi.nlm.nih.gov/pubmed/30745461

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.
https://www.ncbi.nlm.nih.gov/pubmed/27920272

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.
https://www.ncbi.nlm.nih.gov/pubmed/26729813

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.
https://www.ncbi.nlm.nih.gov/pubmed/26488809

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.
https://www.ncbi.nlm.nih.gov/pubmed/26320658

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.
https://www.ncbi.nlm.nih.gov/pubmed/23737552

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.
https://www.ncbi.nlm.nih.gov/pubmed/19731364

Mechanisms of IL-17 Receptor Signaling

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.
http://stke.sciencemag.org/content/sigtrans/11/551/eaat4617.full.pdf?ijkey=9t7OnA3f2T2QU&keytype=ref&siteid=sigtrans

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.
https://www.ncbi.nlm.nih.gov/pubmed/26320658

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.
https://www.ncbi.nlm.nih.gov/pubmed/23737552

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.
https://www.ncbi.nlm.nih.gov/pubmed/20554964

Shen F, Li N, Gade P, Kalvakolanu D, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL. IL-17 receptor signaling inhibits C/EBPb by sequential phosphorylation of the regulatory 2 domain. Science Signaling, 2009; 2:ra8.
https://www.ncbi.nlm.nih.gov/pubmed/19244213

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.
https://www.ncbi.nlm.nih.gov/pubmed/17456598

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.
https://www.ncbi.nlm.nih.gov/pubmed/27798172

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).
https://www.ncbi.nlm.nih.gov/pubmed/22013204