CD4+T help promotes influenza virus-specific CD8+T cell memory by limiting metabolic dysfunction

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8+cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4+T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4+T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8+T cell memory established in the presence or absence of a concurrent CD4+T cell response. We demonstrate that CD4+T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4+T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8+T cells.

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Rapid T Cell Response to Vaccination Can Occur without Antibody Response in Children Post HSCT.

Blood ◽

10.1182/blood.v104.11.2235.2235 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2235-2235

Author(s):

W. Nicholas Haining ◽

J. Evans ◽

N. Seth ◽

G. Callaway ◽

K. Wucherpfennig ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Response ◽

Influenza A ◽

T Cell Response ◽

T Cell Memory ◽

Cell Immunity ◽

Before And After ◽

B Cell Response

Abstract Vaccination is widely used to improve pathogen-specific immunity in patients post HSCT, but it is not known whether patients can mount an effective T cell response to vaccine antigens (vAg). Moreover the relationship between T and B cell response to vAg has not been studied. We hypothesized that a sufficiently sensitive assay of T cell response to vAg would allow vaccination to be used as a tool to measure immune recovery post HSCT and improve vaccine design. We therefore: (1) developed a flow-cytometry-based approach to quantify and characterize T cells specific for vAg; (2) validated it by measuring T cell immunity to influenza A in normal donors; and (3) characterized the T and B cell response to influenza vaccination in pediatric HSCT patients. PBMC were labeled with CFSE and stimulated in vitro with whole influenza Ag. Ag-specific T cells were sensitively detected by their proliferation (loss of CFSE fluorescence) and simultaneous expression of the activation marker HLA-DR. Proliferating/active T cells could be readily detected after stimulation with influenza A Ag in healthy adult (n=4) and pediatric (n=19) donors but were absent in control conditions. Both CD4+ and CD8+ T cell proliferation was detected in all donors but one, and in children as young as 6mo. Staining with MHC I- and MHC II-tetramers confirmed that the proliferating/active population contained T cells specific for immunodominant CD8+ and CD4+ epitopes, demonstrating that vAg were processed and presented to epitope-specific T cells. To characterize the phenotype of influenza-specific T cell memory, we separated memory and naive CD4+ cells prior to antigen-stimulation. Antigen-experienced (CD45RA−/CCR7−) but not naive (CD45RA+/CCR7+) T cells proliferated to vAg confirming that the assay detected pre-existing influenza-A-specific T cell memory. We next assessed Influenza-A-specific T cell immunity before and after influenza vaccination in five pediatric HSCT recipients (mean age 10.6y, range 5–15y; mean time from transplant 13m, range 3–21m). Prior to vaccination the CD4 proliferation to influenza-A was a mean of 3.3% (range 0.04–11%). Following vaccination CD4 proliferation increased significantly in all patients (mean 19.0%, range 6.9%–31.8%, p=0.02). This increase was specific as proliferation to control Ag was unchanged. Influenza-A CD8+ proliferation also increased in 3 of 5 patients but was not statistically significant for the group consistent with the limited efficacy of soluble vAg in inducing CD8+ T cell response. All patients had detectable influenza-A-specific IgG levels prior to vaccination but despite a T cell response to vaccination in all patients, none had a significant increase in IgG level following vaccination. Only one patient had an IgM response; this patient also had the highest influenza-A-specific CD4 proliferation before and after immunization suggesting that there may be a threshold of T cell response required for a B cell response. Using a novel assay we demonstrate that a T cell response to vaccination can occur without an accompanying B cell response. This assay provides a more sensitive measure of immunity to vaccination and allows vaccine response to be used as a benchmark of strategies to accelerate post-HSCT T cell reconstitution.

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Profound Protection against Respiratory Challenge with a Lethal H7N7 Influenza A Virus by Increasing the Magnitude of CD8+ T-Cell Memory

Journal of Virology ◽

10.1128/jvi.74.24.11690-11696.2000 ◽

2000 ◽

Vol 74 (24) ◽

pp. 11690-11696 ◽

Cited By ~ 94

Author(s):

Jan P. Christensen ◽

Peter C. Doherty ◽

Kristen C. Branum ◽

Janice M. Riberdy

Keyword(s):

T Cells ◽

T Cell ◽

Influenza A Virus ◽

Influenza A ◽

Memory T Cells ◽

Influenza Infection ◽

T Cell Memory ◽

Influenza A Viruses ◽

Cell Memory ◽

Cell Pool

ABSTRACT The recall of CD8+ T-cell memory established by infecting H-2b mice with an H1N1 influenza A virus provided a measure of protection against an extremely virulent H7N7 virus. The numbers of CD8+ effector and memory T cells specific for the shared, immunodominant DbNP366epitope were greatly increased subsequent to the H7N7 challenge, and though lung titers remained as high as those in naive controls for 5 days or more, the virus was cleared more rapidly. Expanding the CD8+ memory T-cell pool (<0.5 to >10%) by sequential priming with two different influenza A viruses (H3N2→H1N1) gave much better protection. Though the H7N7 virus initially grew to equivalent titers in the lungs of naive and double-primed mice, the replicative phase was substantially controlled within 3 days. This tertiary H7N7 challenge caused little increase in the magnitude of the CD8+ DbNP366 + T-cell pool, and only a portion of the memory population in the lymphoid tissue could be shown to proliferate. The great majority of the CD8+ DbNP366 + set that localized to the infected respiratory tract had, however, cycled at least once, though recent cell division was shown not to be a prerequisite for T-cell extravasation. The selective induction of CD8+ T-cell memory can thus greatly limit the damage caused by a virulent influenza A virus, with the extent of protection being directly related to the number of available responders. Furthermore, a large pool of CD8+ memory T cells may be only partially utilized to deal with a potentially lethal influenza infection.

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Faculty Opinions recommendation of Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004150.10004 ◽

2001 ◽

Author(s):

JoAnne Flynn

Keyword(s):

T Cell ◽

Differential Regulation ◽

T Cell Immunity ◽

Cd4 T Cell ◽

T Cell Memory ◽

Cell Memory ◽

Cell Immunity

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Faculty Opinions recommendation of Requirement for CD4 T cell help in generating functional CD8 T cell memory.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013631.191506 ◽

2003 ◽

Author(s):

Robert Seder

Keyword(s):

T Cell ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Memory ◽

Cell Memory ◽

Generating Functional ◽

Cd4 T Cell Help ◽

Cd8 T Cell Memory ◽

T Cell Help

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CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

Nature ◽

10.1038/nature03337 ◽

2005 ◽

Vol 434 (7029) ◽

pp. 88-93 ◽

Cited By ~ 425

Author(s):

Edith M. Janssen ◽

Nathalie M. Droin ◽

Edward E. Lemmens ◽

Michael J. Pinkoski ◽

Steven J. Bensinger ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Memory ◽

Cell Memory ◽

Activation Induced Cell Death ◽

Cd4 T Cell Help ◽

Cd8 T Cell Memory ◽

T Cell Help

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Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

10.1101/2021.07.12.21260227 ◽

2021 ◽

Author(s):

Anastasia A Minervina ◽

Mikhail V Pogorelyy ◽

Allison M Kirk ◽

Emma Kaitlynn Allen ◽

Kim J Allison ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

T Cell Responses ◽

T Cell Response ◽

Critical Parameters ◽

T Cell Memory ◽

Cell Memory ◽

Cell Responses ◽

Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

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Protective Memory Responses Are Modulated by Priming Events prior to Challenge

Journal of Virology ◽

10.1128/jvi.01535-09 ◽

2009 ◽

Vol 84 (2) ◽

pp. 1047-1056 ◽

Cited By ~ 10

Author(s):

John A. Rutigliano ◽

Melissa Y. Morris ◽

Wen Yue ◽

Rachael Keating ◽

Richard J. Webby ◽

...

Keyword(s):

T Cell ◽

Influenza A ◽

T Cell Response ◽

H3n2 Virus ◽

Cell Mediated Immunity ◽

Influenza A Viruses ◽

Differential Survival ◽

Virus Challenge ◽

Response Characteristics ◽

H5n1 Influenza

ABSTRACT Human infections with highly pathogenic H5N1 avian influenza A viruses in the last decade have legitimized fears of a long-predicted pandemic. We thus investigated the response to secondary infections with an engineered, but still highly virulent, H5N1 influenza A virus in the C57BL/6 mouse model. Mice primed with the H1N1 A/Puerto Rico/8/34 (PR8) virus were partially protected from lethality following respiratory infection with the modified H5N1 virus A/Vietnam/1203/04 (ΔVn1203). In contrast, those that had been comparably exposed to the HKx31 (H3N2) virus succumbed to the ΔVn1203 challenge, despite similarities in viral replication, weight loss, and secondary CD8+-T-cell response characteristics. All three viruses share the internal genes of PR8 that are known to stimulate protective CD8+-T-cell-mediated immunity. This differential survival of PR8- and HKx31-primed mice was also apparent for antibody-deficient mice challenged with the ΔVn1203 virus. The relative protection afforded by PR8 priming was abrogated in tumor necrosis factor-deficient (TNF−/−) mice, although lung fluids from the B6 HKx31-primed mice contained more TNF early after challenge. These data demonstrate that the nature of the primary infection can influence pathological outcomes following virulent influenza virus challenge, although the effect is not clearly correlated with classical measures of CD8+-T-cell-mediated immunity.

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