IL-33 Augments Virus-Specific Memory T Cell Inflation and Potentiates the Efficacy of an Attenuated Cytomegalovirus-Based Vaccine

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Abstract

Candidate vaccines designed to generate T cell–based immunity are typically vectored by nonpersistent viruses, which largely fail to elicit durable effector memory T cell responses. This limitation can be overcome using recombinant strains of CMV. Proof-of-principle studies have demonstrated the potential benefits of this approach, most notably in the SIV model, but safety concerns require the development of nonreplicating alternatives with comparable immunogenicity. In this study, we show that IL-33 promotes the accumulation and recall kinetics of circulating and tissue-resident memory T cells in mice infected with murine CMV. Using a replication-deficient murine CMV vector, we further show that exogenous IL-33 boosts vaccine-induced memory T cell responses, which protect against subsequent heterologous viral challenge. These data suggest that IL-33 could serve as a useful adjuvant to improve the efficacy of vaccines based on attenuated derivatives of CMV.

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Most cited references 59

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Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention.

Nu Zhang, M Bevan (2013)

Tissue-resident memory T (Trm) cells represent a population of memory CD8⁺ T cells that can act as first responders to local infection. The mechanisms regulating the formation and maintenance of intestinal Trm cells remain elusive. Here we showed that transforming growth factor-β (TGF-β) controlled both stages of gut Trm cell differentiation through different mechanisms. During the formation phase of Trm cells, TGF-β signaling inhibited the migration of effector CD8⁺ T cells from the spleen to the gut by dampening the expression of integrin α4β7. During the maintenance phase, TGF-β was required for the retention of intestinal Trm cells at least in part through the induction of integrins αEβ7 and α1, as well as CD69. Thus, the cytokine acts to control cytotoxic T cell differentiation in lymphoid and peripheral organs. Copyright © 2013 Elsevier Inc. All rights reserved.

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Effector-memory T cell responses are associated with protection of rhesus monkeys from mucosal SIV challenge

Scott G Hansen, Cassandra Vieville, Nathan Whizin … (2009)

The rapid onset of massive, systemic viral replication during primary HIV/SIV infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation1–5. We hypothesized that vaccines designed to maintain differentiated “effector memory” T cell (TEM) responses5,6 at viral entry sites might improve efficacy by impairing viral replication at its earliest stage2, and have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM responses7–9. RhCMV vectors expressing SIV Gag, Rev/Nef/Tat, and Env persistently infected rhesus macaques (RM), regardless of pre-existing RhCMV immunity, and primed and maintained robust SIV-specific, CD4+ and CD8+ TEM responses (characterized by coordinate TNF, IFN-γ and MIP-1β expression, cytotoxic degranulation, and accumulation at extra-lymphoid sites) in the absence of neutralizing antibodies. Compared to control RM, these vaccinated RM showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated, limiting dose, intra-rectal challenge, including four animals that controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development: that vaccines capable of generating and maintaining HIV-specific TEM might decrease the incidence of HIV acquisition after sexual exposure.

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The alarmin interleukin-33 drives protective antiviral CD8⁺ T cell responses.

Christina Schrick, Max Löhning, Padraic Fallon … (2012)

Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

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Author and article information

Journal

Journal ID (nlm-ta): J Immunol

Journal ID (iso-abbrev): J. Immunol

Journal ID (hwp): jimmunol

Journal ID (pmc): jimmunol

Journal ID (publisher-id): JI

Title: The Journal of Immunology Author Choice

Publisher: AAI

ISSN (Print): 0022-1767

ISSN (Electronic): 1550-6606

Publication date (Print): 1 February 2019

Publication date (Electronic): 13 January 2019

Volume: 202

Issue: 3

Pages: 943-955

Affiliations

[* ]Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;

[† ]Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; and

[‡ ]Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom

Author notes

[1]

Current address: Indoor Biotechnologies Ltd., Cardiff, U.K.

[2]

D.A.P. and I.R.H. contributed equally to this work.

J.E.M., M.C., M.M., K.L.M., S.L.-L., E.J.G., A.R., S.G.B., M.A.S., S.J.O., and K.L. performed experiments; E.G. and R.J.S. provided key reagents; J.E.M., M.C., M.A.S., and K.L. analyzed data; J.E.M., D.A.P., and I.R.H. designed the study and wrote the manuscript.

Address correspondence and reprint requests to Dr. James E. McLaren, Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, U.K. E-mail address: mclarenje@ 123456cardiff.ac.uk