Dynamics of CD4+ T Cell Responses against <i>Listeria monocytogenes</i>

Graw, Frederik; Weber, K. Scott; Allen, Paul M.; Perelson, Alan S.

doi:10.4049/jimmunol.1200666

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Other studies have more narrowly focused on CD4+ T cell proliferation [35], TCR signaling [36] or co-stimulatory signals [37]. Our mathematical approach more comprehensively studies the non-cognate interactions (i.e., cytokine milieu) and instructive factors controlling CD4+ T cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

et al. 2013

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Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.

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Section: Discussionmentioning

confidence: 99%

Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

et al. 2013

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“…While the three models reach no consensus on a difference in the rate of memory cell formation in LLO56 and LLO118 cells, LLO56 memory T cells are predicted to have a half-life nearly three times longer than LLO118 memory T cells

. This predicted difference in memory maintenance would explain the better performance of LLO56 during a recall response ( 7 ).…”

Section: Derivation and Characterization Of Listeriolysin O-specific mentioning

confidence: 98%

Functional Heterogeneity in CD4+ T Cell Responses Against a Bacterial Pathogen

Milam

Allen

2015

Front. Immunol.

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To investigate how CD4+ T cells function against a bacterial pathogen, we generated a Listeria monocytogenes-specific CD4+ T cell model. In this system, two TCRtg mouse lines, LLO56 and LLO118, recognize the same immunodominant epitope (LLO190-205) of L. monocytogenes and have identical in vitro responses. However, in vivo LLO56 and LLO118 display vastly different responses during both primary and secondary infection. LLO118 dominates in the primary response and in providing CD8 T cell help. LLO56 predominates in the secondary response. We have also shown that both specific [T cell receptor (TCR)-mediated] and non-specific stimuli (bypassing the TCR) elicit distinct responses from the two transgenics, leading us to conclude that the strength of self-pMHC signaling during development tightly dictates the cell’s future response in the periphery. Herein, we review our findings in this transfer system, focusing on the contribution of the immunomodulatory molecule CD5 and the importance of self-interaction in peripheral maintenance of the cell. We also discuss the manner in which individual TCR affinities to foreign and self-pMHC contribute to the outcome of an immune response; our assertion is that there exists a spectrum of possible T cell responses to recognition of cognate antigen during infection, adding immense diversity to the immune system’s response to pathogens.

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“…We have previously described the derivation and characterization of two Listeria-specific CD4 + T cell transgenic mouse lines, LLO56 and LLO118 (3, 30, 31). These two T cells recognize the same epitope of listeriolysin O (LLO 190-205 ) with the same affinity.…”

Section: Introductionmentioning

confidence: 99%

Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response

Milam

Bartleson

Donermeyer

et al. 2018

The Journal of Immunology

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Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Overexpression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR-self-pMHC interaction and an immune response to infection.

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Dynamics of CD4+ T Cell Responses against Listeria monocytogenes

Cited by 8 publications

References 41 publications

Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

Functional Heterogeneity in CD4+ T Cell Responses Against a Bacterial Pathogen

Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response

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