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 8

Liposomes encapsulating calcitriol and autoantigenic epitopes suppress autoimmune Goodpasture’s vasculitis and reduce antigen-specific CD4+ T cells.

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Liposomes encapsulating calcitriol and autoantigenic epitopes suppress a...
(A) HLA-DR15–transgenic, mouse MHC class II–/– Fcgr2b–/– mice were primed s.c. with α3135–145 in CFA and boosted twice with α3135–145 in IFA. Mice were administered saline, calcitriol/OVA323–339 liposomes, or calcitriol/α3135–145 liposomes s.c. into the tail base on days –14 and –7 (n = 6/group). At day 42, functional renal injury was measured by albuminuria, and glomerular injury was assessed histologically for segmental glomerular necrosis and crescents. Teffs in kidney were enumerated, and DR15-α3135–145 tetramers were used to assess the number of α3135–145–specific intrarenal Foxp3– cells and Foxp3+ CD4+ T cells and the percentage of Foxp3+ CD4+ T cells in spleen. (B) Periodic acid–Schiff (PAS) staining of glomeruli from DR15-transgenic mice: naive, saline, calcitriol/OVA323–339 liposomes, calcitriol/α3135–145 liposomes; representative of 6 mice/group. Accumulation of PAS-positive (pink) stain denote areas of segmental glomerular necrosis, with crescent formation indicated by the accumulation of cells in Bowman’s space (arrows). Original magnification, ×200. (C) Mice (n = 5–6/group) were primed as in A and treated as shown on days 21 and 28. On day 42, glomerular injury was assessed histologically for segmental glomerular necrosis and crescents, and the proportion of α3135–145–specific splenic Foxp3+ CD4+ T cells was enumerated. (D) Experimental conditions as in A but using HLA-DR15–transgenic, mouse MHC class II–/–, Fcgr2b+/+ mice, with assessment on day 10 of pooled spleen and LN for tetramer+ CD44loCD62Lhi naive, CD44hiCD62Llo Tem cells, CXCR5+PD1+ Tfh cells, CD44hiCD62Lhi Tcm cells, CD73+ Tem cells, and Foxp3+ Tregs. IL-17A and IFN-γ production in ILN by ELISPOT after stimulation with α3135–145. *P < 0.05; **P < 0.01; ***P < 0.001 (ANOVA with Tukey’s or Dunnett’s multiple comparison test).