CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

Ahrends, Tomasz; Busselaar, Julia; Severson, Tesa; Bąbała, Nikolina; Vries, Evert de; Bovens, Astrid; Wessels, Lodewyk F.A.; Leeuwen, Fred van; Borst, Jannie

doi:10.1038/s41467-019-13438-1

Cited by 108 publications

(96 citation statements)

References 53 publications

(98 reference statements)

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“…By transcriptomic analyses in mice, we have discovered how help signals impact effector and memory gene expression programs of CD8 + T cells ( 3 , 30 ). At the effector stage, “helped” versus “helpless” CTLs differentially expressed about 1,000 transcripts, encoding proteins enabling critical CTL functions, such as cytotoxicity and migratory abilities.…”

Section: Help Delivery During Cd8 + T Cell Primingmentioning

confidence: 99%

“…CD4 + T cell help delivered during priming optimizes effector differentiation of antigen-specific CD8 + T cells ( 3 , 53 ). Additionally, CD4 + T cell help promotes effector memory CD8 + T cell (T EM ) generation, and renders these T EM cells more effector-like on a per-cell basis ( 30 ). These results are in line with a previously proposed progressive differentiation model for primed CD8 + T cells ( 86 ), adding that CD4 + T cell help shifts differentiation of primed CD8 + T cells toward a more effector-like state ( Figure 4 ) .…”

Section: Helpless Dysfunction Modelmentioning

confidence: 99%

“…By optimizing CTL function, CD4 + T cell help contributes to antigen clearance, which is necessary for proper memory formation ( 87 , 88 ). CD4 + T cell help also promotes the long-term maintenance of T CM cells and is necessary for open configuration of gene loci encoding CTL effector molecules in memory CD8 + T cells ( 30 , 89 , 90 ). The epigenetic imprinting induced by help signals during priming allows memory cells to rapidly exert effector functions upon reactivation in a CD4 + T helper cell-independent manner ( 30 , 91 ).…”

Section: Helpless Dysfunction Modelmentioning

confidence: 99%

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Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion

Busselaar

Tian²,

Eenennaam

et al. 2020

Front. Immunol.

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Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1 + PD-1 + CD8 + T cells as precursors of the terminally exhausted CTL pool. These “predysfunctional” CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4 + T cell help during CD8 + T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide “help” signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4 + T cells in new CD8 + T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.

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Section: Help Delivery During Cd8 + T Cell Primingmentioning

confidence: 99%

Section: Helpless Dysfunction Modelmentioning

confidence: 99%

Section: Helpless Dysfunction Modelmentioning

confidence: 99%

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Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion

Busselaar

Tian²,

Eenennaam

et al. 2020

Front. Immunol.

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“…It is important to note that although the self-peptides were identified using immuneprecipitation of HLA Class-I, it does not restrict the immune response to the self-peptides to CD8+ T cells only. CD4+ T helper cells interact with CD8+ T cells in response to specific antigens to generate effector and memory responses (26), mediated by clustering interactions with a population of dendritic cells (27,28) which optimizes the recall response by memory CD8+ T cells (29).…”

Section: Discussionmentioning

confidence: 99%

Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

et al. 2020

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A significant body of work implicates the adaptive immune response in atherosclerosis, the main underlying cause of coronary artery disease (CAD), yet specific antigens involved remain to be fully identified. The pathobiology of CAD is influenced by sex with many factors that may be involved in the underlying mechanisms. Given the reported sexual dimorphic nature of immune-inflammatory responses, we investigated the influence of sex on potential CAD self-antigens from acute coronary syndrome (ACS) patients using immune-precipitation of soluble HLA Class-I/peptide complexes and mass spectrometry. Relevance of identified self-antigens to atherosclerosis, the major underlying cause of CAD, was tested in the apoE-/-atherosclerotic mouse model. Soluble HLA Class-I complexes from ACS patients and self-reported controls were immune-precipitated and subjected to elution, denaturation and size-exclusion to obtain HLA-bound peptides. Peptides were then subjected to mass spectrometry and patient-unique self-peptides were grouped as common to both female and male, or unique to either sex. Three peptides common to both female and male patients (COL6A1, CDSN, and SAA2), and 2 peptides each unique to female (COL1A1 and COL5A2) or male (SAA1 and KRT 9) patients were selected and mouse homologs of the peptides were screened for self-reactive immune responses in apoE-/-mice. The screening step revealed potential sex-influenced immune responses which was associated with differential immune profiles. Based on the frequency in patient plasma, COL6A1, COL5A2, and KRT 9 peptides were then tested in immunization studies. Neither COL5A2 nor KRT 9 peptide immunization resulted in significant effects on atherosclerosis compared to controls. On the other hand, female mice immunized with COL6A1 peptide had significantly reduced atherosclerosis whereas male mice had significantly increased atherosclerosis, associated with differential immune profiles. Our study identified potential self-antigens involved in atherosclerosis using the immune peptidome of CAD patients. Altering self-reactive immune responses to COL6A1 in apoE-/-mice resulted in differential effects on atherosclerosis burden with sex as a determinant of outcome.

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“…An effective immune response to SARS-CoV-2 involves four types or subsets of T cells: T helper cells (CD4) are responsible for cellular immunity and for helping B cells to produce neutralising antibodies; cytotoxic or killer T cells (CD8) directly kill infected cells—aided by helper T cells2; other T cells (including T-17 (Th17) cells) drive the inflammatory responses that help to control infections3; and regulatory T cells (T regs) help to contain the immune response, to prevent over-reaction and damage to tissues.…”

mentioning

confidence: 99%