PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease
Ryan Galea, Hendrik J. Nel, Meghna Talekar, Xiao Liu, Joshua D. Ooi, Megan Huynh, Sara Hadjigol, Kate J. Robson, Yi Tian Ting, Suzanne Cole, Karyn Cochlin, Shannon Hitchcock, Bijun Zeng, Suman Yekollu, Martine Boks, Natalie Goh, Helen Roberts, Jamie Rossjohn, Hugh H. Reid, Ben J. Boyd, Ravi Malaviya, David J. Shealy, Daniel G. Baker, Loui Madakamutil, A. Richard Kitching, Brendan J. O’Sullivan, Ranjeny Thomas
Ryan Galea, Hendrik J. Nel, Meghna Talekar, Xiao Liu, Joshua D. Ooi, Megan Huynh, Sara Hadjigol, Kate J. Robson, Yi Tian Ting, Suzanne Cole, Karyn Cochlin, Shannon Hitchcock, Bijun Zeng, Suman Yekollu, Martine Boks, Natalie Goh, Helen Roberts, Jamie Rossjohn, Hugh H. Reid, Ben J. Boyd, Ravi Malaviya, David J. Shealy, Daniel G. Baker, Loui Madakamutil, A. Richard Kitching, Brendan J. O’Sullivan, Ranjeny Thomas
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Research Article Nephrology

PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease

Abstract

Autoimmune diseases resulting from MHC class II–restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323–339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323–339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture’s vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.

Authors

Ryan Galea, Hendrik J. Nel, Meghna Talekar, Xiao Liu, Joshua D. Ooi, Megan Huynh, Sara Hadjigol, Kate J. Robson, Yi Tian Ting, Suzanne Cole, Karyn Cochlin, Shannon Hitchcock, Bijun Zeng, Suman Yekollu, Martine Boks, Natalie Goh, Helen Roberts, Jamie Rossjohn, Hugh H. Reid, Ben J. Boyd, Ravi Malaviya, David J. Shealy, Daniel G. Baker, Loui Madakamutil, A. Richard Kitching, Brendan J. O’Sullivan, Ranjeny Thomas

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Figure 7

Liposomes encapsulating calcitriol and autoantigenic epitopes suppress autoimmune arthritis and reduce antigen-specific CD4+ T cells.

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Liposomes encapsulating calcitriol and autoantigenic epitopes suppress a...
(A) For induction of PGIA, BALB/cAnNCrl mice were primed i.p. with rhG1-PG fusion protein and DDA adjuvant and then boosted on days 21 and 42. Mice injected with DDA were used as disease negative controls. Mice were administered 100 μl saline or liposomes as shown s.c. into the tail base on days –14 and –7. Arthritis severity was scored visually based on swelling and redness of the front and hind paws weekly until day 21 and then twice weekly until the endpoint on day 55 (n = 12/group, DDA alone 8/group). Histological scores were evaluated from H&E-stained slides, and PG-specific IgG1 antibodies were quantified by ELISA in sera at the endpoint. Correlation of disease score and aggrecan-specific naive T cells. R2 = 0.3, P < 0.0001. IAd-aggrecan89–103 tetramers were used to assess the proportion of aggrecan89–103-specific CD4+ T cells, tetramer MFI, CD44hiCD62Llo Tem CXCR5+PD1+ Tfh cells, and CD44loCD62Lhi naive and Foxp3+ T cells in spleen. (B) Experimental conditions as in A, with liposomes administered as shown and analysis of proportion of tetramer+ T cells, tetramer MFI, naive and Foxp3–PD1+ T cells, and Foxp3+ Tregs (n = 12/group, DDA alone 8/group). (C) PGIA was induced as in A, and mice were administered 100 μL saline or liposomes as shown s.c. into the tail base on days 32, 36, 40, 44, and 48 (n = 12/group, DDA alone 8/group). (D) Experimental conditions as in C, in which splenocytes from an additional 4 mice in liposome-treated and control groups were restimulated for 7 days with aggrecan89–103 and then analysis of Foxp3+ Tregs and Foxp3–IFN-γ and IL-10+ T cells by flow cytometry. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, ANOVA with Tukey’s multiple comparison test; disease scores compared at endpoint.