Manipulating the TCR signaling network for cellular immunotherapy: Challenges &amp; opportunities

Matson, Courtney A.; Singh, Nevil J.

doi:10.1016/j.molimm.2020.04.007

Cited by 8 publications

(5 citation statements)

References 129 publications

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“…TCR:self-pMHC interactions stimulate tonic or basal TCR signaling in mature T cells in vivo (2), resulting in constitutive tyrosine phosphorylation of the TCR complex and association of the tyrosine kinase ZAP70 with the TCR z-chain (3,4). It has been appreciated that the strength of tonic TCR signaling influences T cell activation, although the mechanisms underlying this phenomenon are incompletely understood (5,6).…”

Section: Introductionmentioning

confidence: 99%

Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells

et al. 2022

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T cells experience varying intensities of tonic or basal TCR signaling in response to self-peptides presented by MHC (self-pMHC) in vivo. We analyzed four subpopulations of mouse naive CD4 + cells that express different levels of Nur77-GFP and Ly6C, surrogate markers that positively and inversely correlate with the strength of tonic TCR signaling, respectively. Adoptive transfer studies suggest that relatively weak or strong Nur77-GFP intensity in thymocytes tends to be maintained in mature T cells. Two-dimensional affinity measurements were lowest for Nur77-GFP lo Ly6C + cells and highest for Nur77-GFP hi Ly6C 2 cells, highlighting a positive correlation between apparent TCR affinity and tonic TCR signal strength. Despite experiencing the strongest tonic TCR signaling, Nur77-GFP hi Ly6C 2 cells were least responsive to multiple concentrations of a cognate or suboptimal pMHC. Gene expression analyses suggest that Nur77-GFP hi Ly6C 2 cells induce a gene expression program that has similarities with that of acutely stimulated T cells. However, strong tonic TCR signaling also correlates with increased expression of genes with inhibitory functions, including coinhibitory receptors. Similarly, assay for transposase-accessible chromatin with sequencing analyses suggested that increased tonic TCR signal strength correlated with increased chromatin accessibility associated with genes that have positive and inhibitory roles in T cell activation. Strikingly, Nur77-GFP hi Ly6C 2 cells exhibited differential accessibility within regions of Cd200r1 and Tox that were similar in location to differentially accessible regions previously identified in exhausted CD8 + T cells. We propose that constitutive strong tonic TCR signaling triggers adaptations detectable at both the transcriptional and epigenetic levels, ultimately contributing to the tuning of T cell responsiveness. ImmunoHorizons, 2022, 6: 671-683.

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Section: Introductionmentioning

confidence: 99%

Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells

et al. 2022

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“…T cell differentiation to IFNg production is disrupted in p40 À/À and p35 À/À mice The biological function of IL-12 in vivo is in promoting the differentiation of IFNg-producing innate and adaptive cells. While there is considerable literature showing how cytokines such as IL-18 and IL-15 as well as T cell receptor (TCR) signaling pathways themselves influence the initial differentiation of IFNg-producing cells (Denton et al, 2007;Matson and Singh, 2020;M€ uller et al, 2001;Tubo and Jenkins, 2014), the role of IL-12 in setting up a feedback loop amplifying this effector mechanism is critical in many responses (Trinchieri, 2003). Immune responses to parasites such as Leishmania are particularly relevant (Park et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo

2021

Self Cite

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“…T cell differentiation to IFNγ production is disrupted in p40 −/− and p35 −/− mice The biological function of IL-12 in vivo is in promoting the differentiation of IFNγ producing innate and adaptive cells. While there is considerable literature showing how cytokines such as IL-18 and IL-15 as well as T cell receptor (TCR) signaling pathways themselves influence the initial differentiation of IFNγ-producing cells (Denton et al, 2007;Matson and Singh, 2020;Müller et al, 2001;Tubo and Jenkins, 2014), the role of IL-12 in setting up a feedback loop amplifying this effector mechanism is critical in many responses (Trinchieri, 2003). Immune responses to parasites such as Leishmania are particularly relevant (Park et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo

Gerber

Singh

2021

The Journal of Immunology

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Cytokines are typically single gene products that potently modify immune responses. The IL-12 family is an exception to this paradigm as these cytokines are heterodimers. In the case of IL-12, the subunits, IL-12p40 and IL-12p35 are encoded by two unlinked genes. However, it is canonical that activated myeloid cells co-express both these subunits simultaneously and secrete a fully active heterodimer of IL-12 which then drives IFNγ production by innate and adaptive cells. Using a chimeric mouse model, we identified a novel method of formation for generating functional IL-12 activity in vivo involving IL-12p40 monomers originating from hematopoietic cells which extracellularly associate with IL-12p35 from other non-hematopoietic cells. In the context of a parasitic challenge, we found that this two-cell mechanism of IL-12 formation was sufficient to drive T cell differentiation in local sites, distal to the initial infection, and thereby regulate systemic dissemination of the pathogen. Accordingly, we identify a new collaboration between hematopoietic and non-hematopoietic cells to produce functional IL-12 through the regulated release of individual subunits as a systemic alert system to prepare host tissues for potential pathogen arrival.

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Manipulating the TCR signaling network for cellular immunotherapy: Challenges & opportunities

Cited by 8 publications

References 129 publications

Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells

Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells

The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo

The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo

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