Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory

Bautista, Bianca; Devarajan, Priyadharshini; McKinstry, K. Kai; Strutt, Tara M.; Vong, Allen M.; Jones, M. C.; Kuang, Yi; Mott, Daniel; Swain, Susan L.

doi:10.4049/jimmunol.1600838

Cited by 38 publications

(94 citation statements)

References 61 publications

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“…4D). CD4 T cells rapidly become resting so day 22 represents a memory time point (50, 58, 59). The percent and numbers of NKG2C/E + ThCTL at 2–3 wk (Fig.…”

Section: Resultsmentioning

confidence: 99%

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Marshall

Vong

Devarajan

et al. 2017

The Journal of Immunology

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CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC-II restricted cytotoxicity. Although CD4 T cell mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show here that in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus (IAV) infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ ThCTL are part of the lung CD4 effector population and they mediate IAV-specific cytotoxic activity. The phenotype of NKG2C/E+ ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet and Blimp-1, and that more of them secrete IFNγ and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity.

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“…4D). CD4 T cells rapidly become resting so day 22 represents a memory time point (50, 58, 59). The percent and numbers of NKG2C/E + ThCTL at 2–3 wk (Fig.…”

Section: Resultsmentioning

confidence: 99%

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Marshall

Vong

Devarajan

et al. 2017

The Journal of Immunology

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“…In fact the APC are short-lived and disappear within 48 h, limiting broader effects. *DC-APC, transferred to adoptive hosts, also present Ag for less than 2 d, so they must play their role early, likely at the initial cognate interaction with naive CD4 T cells (62). …”

Section: Discussionmentioning

confidence: 99%

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Brahmakshatriya

Kuang

Devarajan

et al. 2017

The Journal of Immunology

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Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pre-treated ex vivo with TLR agonists, polyI:C and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG antibody production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond sub-optimally to IL-6 compared to the young, such that higher doses are required to induce comparable signaling. Pre-activating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by pre-activating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised antibody production to inactivated influenza vaccine. These findings reveal a central role for production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation aging CD4 T cell responses shift towards IL-6-independent Th1 and ThCTL responses. Thus, strategies that specifically activate and provide antigen to APC could potentially enhance Ab mediated protection in vaccine responses.

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“…One explanation for reduced memory development in mice where MHC‐II‐dependent interactions are blocked during the effector phase of the CD4 T‐cell response is that autocrine IL‐2 signalling is much reduced. However, TCR stimulation also impacts several aspects of the memory programme that are independent of IL‐2 signalling . Importantly, these experiments used a small number of TCR transgenic donor cells that closely mirrored the response kinetics, and patterns of antigen encounter of endogenous CD4 T cells responding against IAV detected by tetramer analysis .…”

Section: Control Of Cd4 T‐cell Memory During the Effector Phase Of Immentioning

confidence: 99%

Early programming and late‐acting checkpoints governing the development of CD4 T‐cell memory

Dhume

McKinstry

2018

Immunology

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CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T-cell generation into vaccine strategies therefore offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen and co-stimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through 'programming' that occurs during initial priming, and second, through 'checkpoints' that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen- and co-stimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells.

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Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory

Cited by 38 publications

References 61 publications

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Early programming and late‐acting checkpoints governing the development of CD4 T‐cell memory

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