Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

Martin, Aaron J.; Clark, Matthew; Gojanovich, Gregory; Manzoor, Fatima; Miller, Keith R.; Kline, Douglas E.; Morillon, Y. Maurice; Wang, Bo; Tisch, Roland

doi:10.1172/jci.insight.87636

Cited by 6 publications

(29 citation statements)

References 60 publications

(80 reference statements)

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“…The mechanism of this may be similar to what has been seen with use of a non-depleting anti-CD4 mAb, clone YTS177 that activates Rac GTPases and alters trafficking [14]. Further to this point, the non-depleting anti-CD8 mAb, clone YTS105, has also been shown to behave similarly to the aforementioned anti-CD4 mAb where both promote trafficking away from the pancreas and increase numbers of islet-specific T cells in the spleen [15, 16].…”

Section: Resultsmentioning

confidence: 73%

Anti-CD8 monoclonal antibody-mediated depletion alters the phenotype and behavior of surviving CD8+ T cells

et al. 2019

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It is common practice for researchers to use antibodies to remove a specific cell type to infer its function. However, it is difficult to completely eliminate a cell type and there is often limited or no information as to how the cells which survive depletion are affected. This is particularly important for CD8+ T cells for two reasons. First, they are more resistant to mAb-mediated depletion than other lymphocytes. Second, targeting either the CD8α or CD8β chain could induce differential effects. We show here that two commonly used mAbs, against either the CD8α or CD8β subunit, can differentially affect cellular metabolism. Further, in vivo treatment leaves behind a population of CD8+ T cells with different phenotypic and functional attributes relative to each other or control CD8+ T cells. The impact of anti-CD8 antibodies on CD8+ T cell phenotype and function indicates the need to carefully consider the use of these, and possibly other “depleting” antibodies, as they could significantly complicate the interpretation of results or change the outcome of an experiment. These observations could impact how immunotherapy and modulation of CD8+ T cell activation is pursued.

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Section: Resultsmentioning

confidence: 73%

Anti-CD8 monoclonal antibody-mediated depletion alters the phenotype and behavior of surviving CD8+ T cells

et al. 2019

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“…Elevated local levels of IFNγ are believed to establish a feed-forward loop that drives islet pathology. Based on NOD mouse studies, IFNγ secreted by islet CD4 + (and CD8 + ) Teff results in local upregulation of chemotactic cues that induce additional T, B, and innate cells to migrate into the islets, as well as promote islet retention of these effectors ( 109 , 112 ). IFNγ also activates islet resident APC and stromal cells to elevate production of additional inflammatory mediators, such reactive oxygen species, which impair function and mediate β cell necrosis ( 107 , 113 , 114 ).…”

Section: Extrinsic and Intrinsic Factors Promote Pathogenic Effector mentioning

confidence: 99%

“…Notably, the murine IL-21 gene is located in the Idd3 locus and IL-21 receptor (R) deficiency prevents T1D in NOD mice ( 116 ). CD4 + T follicular helper cells, which are increased in the pLN of NOD mice, are the primary source of IL-21 ( 112 , 117 – 119 ). IL-21 has a critical role in supporting B cell development and antibody production.…”

Section: Extrinsic and Intrinsic Factors Promote Pathogenic Effector mentioning

confidence: 99%

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response

2017

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Inflammation is typically induced in response to a microbial infection. The release of proinflammatory cytokines enhances the stimulatory capacity of antigen-presenting cells, as well as recruits adaptive and innate immune effectors to the site of infection. Once the microbe is cleared, inflammation is resolved by various mechanisms to avoid unnecessary tissue damage. Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In type 1 diabetes (T1D), T cells attack the insulin producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by in part altering central and peripheral tolerance inducing events. This results in the development and expansion of β cell-specific effector T cells (Teff) which mediate islet inflammation. Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation. In this review, we will highlight the key events which initiate and sustain T cell-driven pancreatic islet inflammation in nonobese diabetic mice and in human T1D. Specifically, we will discuss: (i) dysregulation of thymic selection events, (ii) the role of intrinsic and extrinsic factors that enhance the expansion and pathogenicity of Teff, (iii) defects which impair homeostasis and suppressor activity of FoxP3-expressing regulatory T cells, and (iv) properties of β cells which contribute to islet inflammation.

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“…The most effective approach may reside in combining strategies functioning via distinct mechanisms. ND Ab specific for CD4 and CD8, for example, can be used to purge pathogenic Teff residing in the islets ( 128 , 133 ). This would then be followed by an antigen-based strategy in which the need to establish a sufficiently sized pool of aTreg becomes less stringent.…”

Section: Discussionmentioning

confidence: 99%

“…A short-course of ND anti-CD4 and -CD8α Ab induces remission in the majority of new onset diabetic NOD mice without affecting systemic T cell numbers ( 128 – 131 ). Induction of remission is due to Ab-mediated crosslinking of the CD4 and CD8 molecules, which reduces TCR signaling as well as upregulates additional signaling pathways ( 128 , 131 – 133 ). The result is suppressed expression of proinflammatory cytokines by Teff combined with the induction of a promigratory phenotype that drives pancreatic egress of Teff ( 128 , 133 ).…”

Section: Antigen-independent Immunotherapiesmentioning

confidence: 99%

Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes

et al. 2018

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Type 1 diabetes (T1D) is an autoimmune disease that is generally considered to be T cell-driven. Accordingly, most strategies of immunotherapy for T1D prevention and treatment in the clinic have targeted the T cell compartment. To date, however, immunotherapy has had only limited clinical success. Although certain immunotherapies have promoted a protective effect, efficacy is often short-term and acquired immunity may be impacted. This has led to the consideration of combining different approaches with the goal of achieving a synergistic therapeutic response. In this review, we will discuss the status of various T1D therapeutic strategies tested in the clinic, as well as possible combinatorial approaches to restore β cell tolerance.

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Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

Cited by 6 publications

References 60 publications

Anti-CD8 monoclonal antibody-mediated depletion alters the phenotype and behavior of surviving CD8+ T cells

Anti-CD8 monoclonal antibody-mediated depletion alters the phenotype and behavior of surviving CD8+ T cells

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response

Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes

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