Role of antigen persistence and dose for CD4<sup>+</sup>T-cell exhaustion and recovery

Han, Shaobo; Asoyan, Ayuna; Rabenstein, Hannah; Nakano, Naoko; Obst, Reinhard

doi:10.1073/pnas.1008437107

Cited by 124 publications

(134 citation statements)

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“…Interestingly, following repeated stimulation of OT-II CD4 ϩ T cells in vitro via the TCR, using splenocytes presenting OVA peptide, we also saw less downregulation of T cell function (measured by IL-2 secre- Infection and Immunity tion), without differences in the upregulation of LAG-3 and PD-1 ( Fig. S3), similar to our observations during T cell exhaustion induced by P. yoelii, lending support to the idea that modulation of the response to chronic antigen-specific stimulation of the TCR is central to the role of NFAT1 in the regulation of the T cell exhaustion phenotype (22,23). Increased protection against lethal P. yoelii OVA infection is conferred by adoptive transfer of Nfat1 ؊/؊ CD4 ؉ T cells.…”

Section: Resultssupporting

confidence: 78%

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

et al. 2017

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Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1-deficient CD4 ϩ T cells maintain higher proliferative capacity and expression of effector cytokines following Plasmodium yoelii infection and are therefore more resistant to P. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4 ϩ T cells following P. yoeliiinduced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4 ϩ T cells into mice infected with P. yoelii results in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses during Plasmodiuminduced CD4 ϩ T cell exhaustion.

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Section: Resultssupporting

confidence: 78%

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

et al. 2017

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“…T-cell exhaustion is common in situations of chronic exposure to antigen, but in immunocompetent mice L. monocytogenes is rapidly cleared (27). Although LLO118 cells do have slight upregulation of PD-1 and CTLA-4, they do not exhibit classic signs of exhaustion, such as dramatically increased levels of PD-1 (28). LLO118 T cells have TCR levels that are down-regulated significantly and for an extended period.…”

Section: Discussionmentioning

confidence: 99%

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

Weber

Persaud

et al. 2012

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

114

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Helper T cells are critical for protective immunity, CD8 + T-cell memory, and CD4 + recall responses, but whether the same or distinct CD4 + T cells are involved in these responses has not been established. Here we describe two CD4 + T cells, LLO118 and LLO56, specific for an immunodominant Listeria monocytogenes epitope, with dramatically different responses to primary and secondary infection. Comparing in vivo responses, LLO118 T cells proliferate more strongly to primary infection, whereas surprisingly, LLO56 has a superior CD4 + recall response to secondary infection. LLO118 T cells provide more robust help for CD8 + T-cell responses to secondary infection than LLO56. We found no detectable differences in antigen sensitivity, but naive LLO118 T cells have much lower levels of CD5 and their T-cell receptor levels are dramatically down-regulated after their strong primary response. Thus, distinct CD4 + helper T cells are specialized to help either in primary or secondary responses to infection.infectious disease | affinity | T-cell receptor transgenic mice | apoptosis C D4 + T cells are essential for CD8 + memory-cell formation, recall responses, and protective immunity (1-3). Despite the importance of CD4 + T cells in immune responses, studies examining T-cell responses to Listeria monocytogenes have focused primarily on CD8 + T cells (4). CD4 + T cells are not required for the primary CD8 + response to L. monocytogenes, but they play a critical role in the maintenance and survival of CD8 + memory cells (1-5). Memory cell formation is a hallmark of the adaptive immune system and successful memory cells must navigate expansion, contraction, and maintenance (6). Much more has been learned about the pathways for formation of CD8 + memory cells than CD4 + memory cells, but it is clear that the pathways for CD4 + memory formation are distinct (6-8). The parameters of optimal CD4 + help for CD8 + and CD4 + memory formation have not been characterized and represent an opportunity to effectively improve vaccines (9).T cells with shortened exposure to antigen do not successfully differentiate to memory cells (10). In contrast, overstimulation in a situation like chronic infection leads to T-cell exhaustion and ineffective memory cell formation or persistence (11). Thus, there appears to be a "goldilocks" level of T-cell stimulation for effective memory cell formation (6). Differences in the duration or abundance of antigen presentation or costimulatory molecules alter activation levels and T-cell receptor (TCR) levels and regulators on the T cell itself affect activation levels (12). TCR affinity and thymic development can also alter T-cell antigen sensitivity (13). For example, the surface expression of one Tcell-negative regulator of T-cell activation, CD5, correlates with the affinity of that developing TCR for self peptide (14-16). The relationship between effective CD4 + responses and the avidity of the TCR:pMHC interaction is not established and a polyclonal CD4 + T-cell population is not amenable to address the...

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“…6) also impact on CD8 + T-cell exhaustion. Also in case of CD4 + T cells, it was recently shown that prolonged high-level antigen expression on MHC class II induces CD4 + T-cell exhaustion with the level of antigen exposure influencing the kinetics of CD4 + T-cell dysfunction [46].Unexpectedly, DC-MHCI mice developed disease symptoms after transfer of 10 4 TCR transgenic CD8 + T cells and low-dose LCMV infection, presumably due to their failure to control infection. In addition, DC-MHCI mice succumbed to infection after adoptive CD8 + T-cell transfer and high-dose LCMV infection using CD8 + T-cell numbers where wild-type recipients stayed healthy.…”

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confidence: 99%

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

2012

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Chronic viral infections lead to CD8 + T-cell exhaustion, characterized by impaired cytokine secretion and loss of proliferative capacity. While viral load and T-cell dysfunction correlate, it is currently unclear whether the quality of a cell type presenting antigen determines the degree of T-cell exhaustion or if the overall amount of antigen recognized by T cells promotes exhaustion. We found that chronic lymphocytic choriomeningitis virus infection led to decreased CD8 + T-cell exhaustion in DC-MHC class I (MHCI) mice, in which CD8 IntroductionDuring highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hierCorrespondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13]. Infection of mice with a low dose of the same virus strains results in an acute resolved infection [13].Besides a role for immunoregulatory cytokines such as 15], , a role for inhibitory receptor expression (reviewed in [18]) and perhaps regulatory T cells [19] C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2290-2304 HIGHLIGHTS 2291as well as the availability of T-cell help [10,20] and , the overall duration and amount of antigen exposure seems to be a critical parameter driving CD8 + T-cell exhaustion. Recent work has highlighted a negative correlation between viral load and CTL function in chronically infected humans and mice [24][25][26][27]. Even though these studies indicate that high overall antigen levels correlate with T-cell exhaustion, it was never directly shown whether alterations of antigen levels can substantially influence T-cell function independently of the cell type presenting the antigen in vivo. Furthermore, as T-cell exhaustion and viral persistence mutually depend on each other and since alterations in one of the parameters affects the other one, it is often difficult to assign causal relationships, particularly in humans.Here, we made use of Tg(CD11c-β2m) × Tg(K14-β2m) × β2m −/− (DC-MHCI, where DC is defined as dendritic cell; MHCI is defined as MHC class I) mice to assess the role of antigen presenting cells versus antigen load in induction of CD8 + T-cell exhaustion upon chronic LCMV infection. DC-MHCI mice are β2m −/− mice that transgenically express β2m in DCs, keratinocytes, and thymic cortical epithelial cells, ensuring positive selection of CD8 + T cells in the thymus [28]. Thus, DC-MHCI mice can mount normal endogenous CD8 + T-cell responses, but peripheral CD8 + T cells can o...

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Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

Cited by 124 publications

References 59 publications

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

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Role of antigen persistence and dose for CD4+T-cell exhaustion and recovery

Cited by 124 publications

References 59 publications

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

Distinct CD4 + helper T cells involved in primary and secondary responses to infection

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

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Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

The Transcription Factor NFAT1 Participates in the Induction of CD4⁺T Cell Functional Exhaustion during Plasmodium yoelii Infection

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell