Heat shock proteins can be targets of regulatory T cells for therapeutic intervention in rheumatoid arthritis

Figures & data

Table I. Treg-associated makers expressed on T cells responsive to HSP. All markers depicted were identified on CD4+ HSP-responsive T cells that were functionally tested for suppressive capacity in vitro (e.g. suppression assay), or in vivo (adoptive transfer).

Molecule	Function	Hsp	Model (of disease)
CD25	IL-2 receptor alpha chain	Hsp40	JIA [75], none [76], lung cancer [68,77]
		Hsp60	AA [50,78], AD [79], atherosclerosis [69], DTH [58], filariasis [41], infection [58], none [66,80–82]
		Hsp70	PGIA [27], none [83]
		Hsp90	EAE [67], cancer [84]
CD27	TNF receptor	Hsp60	None [56]
		Hsp70	None [83]
CD28	Co-stimulatory molecule	Hsp60	AA [85]
CD30	TNF receptor	Hsp60	None [56]
CD45RA	On naive cells	Hsp60	None [80]
CD45RO	On memory cells	Hsp60	None [80]
CD69	Activation marker	Hsp40	JIA [75]
CD86	Co-stimulatory molecule	HS APC	AA [62]
CTLA-4	Co-stimulatory molecule	Hsp40	JIA [75]
		Hsp60	None [56]
		Hsp70	None [83]
FoxP3	Transcription factor	Hsp40	RA [49,74], none [76]
		Hsp60	AA [50,78], AD [79], atherosclerosis [69], none [56,66,80]
		Hsp70	PGIA [27]
		Hsp90	Cancer [84]
GITR	Co-stimulatory molecule	Hsp60	None [56]
IL-4	Th2 cytokine	HS APC	AA [62]
		Hsp70	AA [63], CIA [43]
IL-5	Th2 cytokine	Hsp70	CIA [43]
IL-10	Anti-inflammatory cytokine	HS APC	AA [62]
		Hsp40	JIA [75]
		Hsp60	AA [86], atherosclerosis [69], DTH [58], infection [58], none [56,80]
		Hsp70	AA [63], CIA [43], listeriosis [39], PGIA [27]
IL-13	Th2 cytokine	Hsp60	None [80]
LAG-3	Inhibitory molecule	Hsp70	PGIA [27]
Nrp-1	Inhibitory molecule	Hsp70	PGIA [27]
TGF-β	Anti-inflammatory cytokine	Hsp60	AA [85–87], DTH [58], infection [58]
		Hsp70	Listeriosis [39]

AA, adjuvant arthritis (rat); AD, atopic dermatitis (human); CIA, collagen-induced arthritis (mouse); CTLA-4, cytotoxic T-lymphocyte antigen 4; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; FoxP3, forkhead box P3; GITR, glucocorticoid-induced TNFR family-related gene; Hsp, Heat shock protein; HS APC, heat-shocked antigen presenting cells; IL, interleukin; JIA, juvenile idiopathic arthritis (human); LAG-3, lymphocyte-activation gene 3; None, studies performed without inducing disease; Nrp-1, Neuropilin-1; PGIA, proteoglycan-induced arthritis (mouse); RA, rheumatoid arthritis (human); TGF-β, transforming growth factor beta.

Massa M, Passalia M, Manzoni SM, Campanelli R, Ciardelli L, Yung GP, et al. Differential recognition of heat-shock protein DnaJ-derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis. Arthritis Rheum 2007;56:1648–57

 PubMed Web of Science ®Google Scholar

Nishikawa H, Kato T, Tawara I, Saito K, Ikeda H, Kuribayashi K, et al. Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells. J Exp Med 2005;201:681–6

 PubMed Web of Science ®Google Scholar

Nishikawa H, Kato T, Tawara I, Takemitsu T, Saito K, Wang L, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci USA 2005;102:9253–7

 PubMed Web of Science ®Google Scholar

Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci USA 2003;100:10902–6

 PubMed Web of Science ®Google Scholar

Roord ST, Zonneveld-Huijssoon E, Le T, Yung GP, Koffeman E, Ronaghy A, et al. Modulation of T cell function by combination of epitope specific and low dose anticytokine therapy controls autoimmune arthritis. PLoS One 2006;1:e87

 PubMed Web of Science ®Google Scholar

Dominguez MC, Lorenzo N, Barbera A, Darrasse-Jeze G, Hernandez MV, Torres A, et al. An altered peptide ligand corresponding to a novel epitope from heat-shock protein 60 induces regulatory T cells and suppresses pathogenic response in an animal model of adjuvant-induced arthritis. Autoimmunity 2011;44:471–82

 PubMed Web of Science ®Google Scholar

Kapitein B, Aalberse JA, Klein MR, de JW, Hoekstra MO, Knol EF, et al. Recognition of self-heat shock protein 60 by T cells from patients with atopic dermatitis. Cell Stress Chaperones 2013;18:87–95

 PubMed Web of Science ®Google Scholar

Yang K, Li D, Luo M, Hu Y. Generation of HSP60-specific regulatory T cell and effect on atherosclerosis. Cell Immunol 2006;243:90–5

 PubMed Web of Science ®Google Scholar

Wang X, Zhou S, Chi Y, Wen X, Hoellwarth J, He L, et al. CD4+CD25+ Treg induction by an HSP60-derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent. Eur J Immunol 2009;39:3052–65

 PubMed Web of Science ®Google Scholar

Shiny C, Krushna NS, Babu S, Elango S, Manokaran G, Narayanan RB. Recombinant Wolbachia heat shock protein 60 (HSP60) mediated immune responses in patients with lymphatic filariasis. Microbes Infect 2011;13:1221–31

 PubMed Web of Science ®Google Scholar

van Herwijnen MJ, Wieten L, van der Zee R, van Kooten PJ, Wagenaar-Hilbers JP, Hoek A, et al. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc Natl Acad Sci USA 2012;109:14134–9

 PubMed Web of Science ®Google Scholar

Corrigall VM, Vittecoq O, Panayi GS. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development. Immunology 2009;128:218–26

 PubMed Web of Science ®Google Scholar

Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava P. Immune modulation with high-dose heat-shock protein gp96: Therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 2004;16:615–24

 PubMed Web of Science ®Google Scholar

Liu Z, Li X, Qiu L, Zhang X, Chen L, Cao S, et al. Treg suppress CTL responses upon immunization with HSP gp96. Eur J Immunol 2009;39:3110–20

 PubMed Web of Science ®Google Scholar

de Kleer I, Vercoulen Y, Klein M, Meerding J, Albani S, van der Zee R, et al. CD30 discriminates heat shock protein 60-induced FOXP3+ CD4+ T cells with a regulatory phenotype. J Immunol 2010;185:2071–9

 PubMed Web of Science ®Google Scholar

Quintana FJ, Mimran A, Carmi P, Mor F, Cohen IR. HSP60 as a target of anti-ergotypic regulatory T cells. PLoS One 2008;3:e4026

 PubMed Web of Science ®Google Scholar

Aalberse JA, Kapitein B, de RS, Klein MR, de JW, van der Zee R, et al. Cord blood CD4+ T cells respond to self heat shock protein 60 (HSP60). PLoS One 2011;6:e24119

 PubMedGoogle Scholar

Paul AG, van Kooten PJ, van EW, van der Zee R. Highly autoproliferative T cells specific for 60-kDa heat shock protein produce IL-4/IL-10 and IFN-gamma and are protective in adjuvant arthritis. J Immunol 2000;165:7270–7

 PubMed Web of Science ®Google Scholar

Koffeman EC, Genovese M, Amox D, Keogh E, Santana E, Matteson EL, et al. Epitope-specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial. Arthritis Rheum 2009;60:3207–16

 PubMed Web of Science ®Google Scholar

Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, et al. Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci USA 2004;101:4228–33

 PubMed Web of Science ®Google Scholar

Ohue R, Hashimoto K, Nakamoto M, Furukawa Y, Masuda T, Kitabatake N, et al. Bacterial heat shock protein 60, GroEL, can induce the conversion of naive T cells into a CD4 CD25(+) Foxp3-expressing phenotype. J Innate Immun 2011;3:605–13

 PubMed Web of Science ®Google Scholar

Prakken BJ, Wendling U, van der Zee R, Rutten VP, Kuis W, van EW. Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins. J Immunol 2001;167:4147–53

 PubMed Web of Science ®Google Scholar

Brownlie RJ, Myers LK, Wooley PH, Corrigall VM, Bodman-Smith MD, Panayi GS, et al. Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells: A novel function for an ancient protein. Arthritis Rheum 2006;54:854–63

 PubMedGoogle Scholar

Durai M, Gupta RS, Moudgil KD. The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis. J Immunol 2004;172:2795–802

 PubMed Web of Science ®Google Scholar

Kimura Y, Yamada K, Sakai T, Mishima K, Nishimura H, Matsumoto Y, et al. The regulatory role of heat shock protein 70-reactive CD4+ T cells during rat listeriosis. Int Immunol 1998;10:117–30

 PubMed Web of Science ®Google Scholar