Durable CD4 T-Cell Memory Generation Depends on Persistence of High Levels of Infection at an Effector Checkpoint that Determines Multiple Fates

Swain, Susan L.; Jones, M. C.; Devarajan, Priyadharshini; Xia, Jingya; Dutton, Richard; Strutt, Tara M.; McKinstry, K. Kai

doi:10.1101/cshperspect.a038182

Cited by 10 publications

(10 citation statements)

References 58 publications

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“…Extending the period of Ag presentation also promoted enhanced CD4 and CD8 memory formation (2–4, 23, 24, 57, 58). The pathways responsible were not determined and no studies restricted Ag to the effector checkpoint, that we know is strictly required for memory generation (23, 24, 47). Our study is the first to analyze the effect of a broad range of affinities during the effector checkpoint on memory.…”

Section: Discussionmentioning

confidence: 99%

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Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

Jones

Castonguay

Nanaware

et al. 2022

Preprint

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The impact of initial peptide antigen affinity for TCR in driving memory fate has been studied previously, however its contributions when effectors contract to memory is unclear. To become memory, effector CD4 T cells must recognize antigen at 5-8 days post-infection, at what we call the “effector checkpoint.” We examined whether peptide affinity for the TCR of effectors impacts the extent of memory and degree of protection against rechallenge. We made an influenza A virus (IAV) nucleoprotein (NP)-specific TCR transgenic strain, FluNP, and generated NP-peptide variants that bind FluNP TCR with a broad range of avidity. To vary avidity in vivo, we primed naïve donor FluNP in IAV-infected hosts, purified 6d FluNP effectors and co-transferred them with peptide-pulsed APC into uninfected second hosts. Higher affinity peptides yielded higher numbers of FluNP memory cells in the spleen and most dramatically in the lung and dLN, and drove better protection against lethal influenza infection. The major impact of avidity was on memory cell number, not cytokine production, and was already apparent within several days of transfer. We previously showed that autocrine IL-2 production during the effector checkpoint prevented default effector apoptosis and supported memory formation. Here, peptide avidity determined the level of IL-2 produced by effectors. IL-2Rα expression by APC drove more memory cell formation, suggesting that transpresentation of IL-2 by APC at this checkpoint enhanced CD4 memory generation. Secondary memory generation was also avidity-dependent. We propose this pathway selects CD4 effectors of highest affinity to progress to memory.

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Section: Discussionmentioning

confidence: 99%

“…4A). At 4-8 dpi, the time when autocrine IL-2 signals are needed for CD4 T cell memory (47), substantial populations of CD11c + , MHC-II + cells express CD25 in the lung, dLN and spleen (Fig 4B ).…”

Section: Cd25 Expression On Apc During the Effector Phase Promotes Ef...mentioning

confidence: 99%

Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

Jones

Castonguay

Nanaware

et al. 2022

Preprint

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“…We previously established that cognate Ag recognition by CD4 effectors and autocrine IL-2 induction is required for generation of protective CD4 memory, and that these signals are required by CD4 effectors at 6-8 dpi (Bautista et al, 2016; McKinstry et al, 2014; Swain et al, 2021). Recently we showed that T FH development during IAV infection required cognate Ag recognition by CD4 effectors in the SLO (Devarajan et al, 2022), and signals from CD28 co-stimulation.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15

Devarajan

Vong

Castonguay

et al. 2020

Preprint

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SummaryT follicular helper (TFH) and Cytotoxic CD4 (ThCTL) are tissue-restricted CD4 effector subsets, functionally specialized to mediate optimal Ab production and cytotoxicity of infected cells. Influenza infection generates robust CD4 responses, including lung ThCTL and SLO TFH, that protect against reinfection by variant strains. Antigen (Ag) presentation after infection, lasts through the effector phase of the response. Here, we show that this effector phase Ag presentation, well after priming, is required to drive CD4 effectors to ThCTL and TFH. Using in vivo influenza models, we varied Ag presentation to effectors acutely, just at the effector phase. Ag presentation was required in the tissue of effector residence. We suggest these requirements contain unnecessary or potentially pathogenic CD4 responses, only allowing them if infection is uncleared. The results imply that providing effector phase Ag, would lead to stronger humoral and CD4 tissue immunity and thus can be applied to improve vaccine design.

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“…However, when we introduced APC activated with pathogen-recognition (PR) signals and pulsed with the peptide antigen, memory was fully restored ( 19 ). Memory generation depended on CD4 effector (autocrine) IL-2 production for 3 days beginning as effectors were generated ( 20 ), defining a checkpoint for memory. This reduced the programmed cell death of effectors and restored robust donor CD4 memory that protected the uninfected hosts from re-challenge ( 18 – 20 ).…”

Section: Background and Recent Studiesmentioning

confidence: 99%

CD4 memory has a hierarchical structure created by requirements for infection-derived signals at an effector checkpoint

Swain

2023

Front. Immunol.

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Our recent studies reveal that the persistence, location, and amount of both antigen and signals that induce pathogen recognition responses determine the number of CD4 memory cells, the subsets that develop, their location, and hence their protective efficacy. Non-replicating vaccines provide antigen that is short-lived and generate low levels of only some memory subsets that are mostly restricted to secondary lymphoid tissue. In contrast, exposure to long-lived replicating viruses and bacteria provides high levels of diverse antigens in sites of infection and induces strong pathogen recognition signals for extended periods of time, resulting in much higher levels of memory cells of diverse subsets in both lymphoid and nonlymphoid sites. These include memory subsets with highly potent functions such as T follicular helpers and cytotoxic CD4 effectors at sites of infection, where they can most effectively combat the pathogen early after re-infection. These effectors also do not develop without antigen and pathogen recognition signals at the effector stage, and both subsets must receive these signals in the tissue sites where they will become resident. We postulate that this leads to a hierarchical structure of memory, with the strongest memory induced only by replicating pathogens. This paradigm suggests a likely roadmap for markedly improving vaccine design.

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Durable CD4 T-Cell Memory Generation Depends on Persistence of High Levels of Infection at an Effector Checkpoint that Determines Multiple Fates

Cited by 10 publications

References 58 publications

Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15

CD4 memory has a hierarchical structure created by requirements for infection-derived signals at an effector checkpoint

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