Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms

McKinstry, K. Kai; Strutt, Tara M.; Kuang, Yi; Brown, Deborah M.; Sell, Stewert; Dutton, Richard; Swain, Susan L.

doi:10.1172/jci63689

Cited by 207 publications

(258 citation statements)

References 47 publications

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“…The loss of protection observed upon depletion of transferred memory CD4 + T cells, even though help was unchanged, suggests that the enhanced abilities of 2°effectors as compared with 1°effectors are a major component of the protection conferred by memory CD4 + T cells. Our results thus provide a basis for understanding the protection mediated by memory CD4 + T cells in B-cell-deficient, CD8 + T-cell-deficient, and even lymphocyte-deficient hosts challenged with IAV (11,12). Second, we find that effectors in the spleen, dLN, and lung are strikingly different from one another, suggesting that they are specialized to perform unique functions at different sites.…”

Section: Discussionmentioning

confidence: 60%

“…Our data are consistent with the hypothesis that effectors in the lung are important for protection against IAV through direct mediation of viral clearance. How CD4 + T-cell effectors combat IAV is not fully understood, but our studies suggest that individual protective mechanisms, including perforin-dependent killing of infected cells and production of IFN-γ, become more or less important depending on the context of infection (8,12). In contrast, the expression of T FH -associated genes in 1°effectors was restricted to SLO, but 2°e ffectors contained substantial T FH populations in all organs tested.…”

Section: Discussionmentioning

confidence: 82%

“…The transfer of 1°effectors to unprimed mice can protect against lethal challenge (8)(9)(10), and studies demonstrating memory CD4 + T-cell protection in mice deficient for CD8 + T and B cells suggest that an important helper-independent protective contribution of memory CD4 + T cells may be mediated directly by the 2°e ffectors (11)(12)(13). In addition, IAV-specific 1°effector (7,10) and memory (14,15) CD4 + T cells isolated from the lung and from secondary lymphoid organs (SLO) display distinct functional and phenotypic characteristics.…”

Section: Cytokines | Viral Infection | Immune Regulationmentioning

confidence: 99%

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Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Strutt

McKinstry

Kuang

et al. 2012

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

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112

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Whether differences between naive cell-derived primary (1°) and memory cell-derived secondary (2°) CD4+ T-cell effectors contribute to protective recall responses is unclear. Here, we compare these effectors directly after influenza A virus infection. Both develop with similar kinetics, but 2° effectors accumulate in greater number in the infected lung and are the critical component of memory CD4+ T-cell–mediated protection against influenza A virus, independent of earlier-acting memory-cell helper functions. Phenotypic, functional, and transcriptome analyses indicate that 2° effectors share organ-specific expression patterns with 1° effectors but are more multifunctional, with more multicytokine (IFN-γ+/IL-2+/TNF+)-producing cells and contain follicular helper T-cell populations not only in the spleen and draining lymph nodes but also in the lung. In addition, they express more CD127 and NKG2A but less ICOS and Lag-3 than 1° effectors and express higher levels of several genes associated with survival and migration. Targeting two differentially expressed molecules, NKG2A and Lag-3, reveals differential regulation of 1° and 2° effector functions during pathogen challenge.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 82%

Section: Cytokines | Viral Infection | Immune Regulationmentioning

confidence: 99%

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Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Strutt

McKinstry

Kuang

et al. 2012

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

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112

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“…We therefore generated rested effector cells, which resemble memory cells in their transcriptome, physiology, and function (43,55), and tested whether their response to transient Ag presentation, as described for Supplemental Fig. 1, differs from naive cells.…”

Section: Ag-independent Cd4 + T Cell Proliferation Is Not Affected Bymentioning

confidence: 99%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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“…More specifically, memory CD4 + T cells promote viral clearance through a variety of synergizing mechanisms, including Thmediated perforin cytotoxicity and the enhancement of B-cell and CD8 + T-cell responses (8)(9)(10). T-cell priming by dendritic cells (DCs) is a pivotal process for the acquisition of T-cell memory that largely influences the strength and efficiency of recall immune responses after subsequent virus infections (11)(12)(13).…”

mentioning

confidence: 99%

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

Céspedes

Bueno

Ramírez

et al. 2014

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

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Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse-and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4 + T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell− bilayer interface, suggesting that N protein interferes with pMHC− TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.

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Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms

Cited by 207 publications

References 47 publications

Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

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Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms

Cited by 207 publications

References 47 publications

Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

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Product

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Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

Memory CD4⁺T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors