A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

Belyakov, Igor M.; Isakov, Dmitry V.; Zhu, Qing; Dzutsev, Amiran; Berzofsky, Jay A.

doi:10.4049/jimmunol.178.11.7211

Cited by 91 publications

(107 citation statements)

References 77 publications

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“…Consistent findings were observed in our previous studies where, of two cohorts of SIV/HIV-infected macaques, one of four in the first cohort (4,36) and three of four in the second cohort (5) in the adjuvant-only group failed to get infected. We identified that the enhanced A3G expression was widely distributed in DCs, monocyte/macrophage, and CD4 + T cells.…”

Section: Discussionsupporting

confidence: 76%

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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110

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Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8 + T cells correlated with protection, not tetramer + T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Rα, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity.

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Section: Discussionsupporting

confidence: 76%

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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110

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“…IFN-␥ production in T cells was measured after restimulated with proper peptides. Intracellular cytokines was measured in DCs after stimulation with TLR ligands (49). ELISA or multiplex systems were used to determine cytokine production in DC supernatants.…”

Section: Animals and Reagentsmentioning

confidence: 99%

Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines

Zhu

Egelston

Aravindhan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Toll-like receptors (TLRs) may need to cooperate with each other to be effective in detecting imminent infection and trigger immune responses. Understanding is still limited about the intracellular mechanism of this cooperation. We found that when certain TLRs are involved, dendritic cells (DCs) establish unidirectional intracellular cross-talk, in which the MyD88-independent TRIF-dependent pathway amplifies the MyD88-dependent DC function through a JNK-dependent mechanism. The amplified MyD88-dependent DC function determines the induction of the T cell response to a given vaccine in vivo. Therefore, our study revealed an underlying TLR mechanism governing the functional, nonrandom interplay among TLRs for recognition of combinatorial ligands that may be dangerous to the host, providing important guidance for design of novel synergistic molecular vaccine adjuvants.HIV ͉ innate immunity ͉ adjuvants ͉ MyD88 ͉ TRIF

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“…However, generation and survival of antigen-specific CD8 1 T cells after i.r. immunization is not well understood [10,51,52]. In this study, we continued to characterize: (i) the kinetics of CD8 1 T-cell responses in the gut after i.r.…”

Section: Discussionmentioning

confidence: 99%

“…SI-IEL cells and LP lymphocytes from mice were isolated as described previously with a minor modification [52].…”

Section: Viruses and Immunization Protocolmentioning

confidence: 99%

Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8⁺ T cells

et al. 2011

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Survival of antigen-specific CD8+ T cells in peripheral lymphoid organs during viral infection is known to be dependent predominantly on IL-7 and IL-15. However, little is known about a possible influence of tissue environmental factors on this process. To address this question we studied survival of memory antigen-specific CD8+ T cells in the small intestine. Here, we show that 2 months after vaccinia virus infection, B8R20–27/H2-Kb tetramer+ CD8+ T cells in the small intestinal intraepithelial (SI-IEL) layer are found in mice deficient in IL-15 expression. Moreover, SI-IEL and lamina propria lymphocytes do not express the receptor for IL-7 (IL-7Rα/CD127). In addition, after in vitro stimulation with B8R20–27 peptide, SI-IEL cells do not produce high amounts of IFN-γ either at 5 days (5d) or at 2 months post infection (p.i.). Importantly, the lack of IL-15 was found to shape the functional activity of antigen-specific CD8+ T cells, by narrowing the CTL avidity repertoire. Taken together, these results reveal that survival factors as well as functional activity of antigen-specific CD8+ T cells in the SI-IEL compartments may markedly differ from their counterparts in peripheral lymphoid tissues.

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A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

Cited by 91 publications

References 77 publications

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines

Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8⁺ T cells

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A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

Cited by 91 publications

References 77 publications

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines

Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8+ T cells

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Product

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Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8⁺ T cells