Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation

Elzey, Bennett D.; Grant, Julieann F.; Sinn, Haley W.; Nieswandt, Bernhard; Waldschmidt, Thomas J.; Ratliff, Timothy L.

doi:10.1189/jlb.1104669

Cited by 92 publications

(89 citation statements)

References 26 publications

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“…[18][19][20][21] We also reported the ability of WT platelets to enhance IgG production, and in concert with WT CD4 T cells, to enhance GC formation in CD154 knockout mice. 18,22 Importantly, we showed that in response to low doses of antigen, WT mice cannot produce normal levels of IgG in the absence of platelets. Accordingly, we have proposed that platelets perform a sentinel function for adaptive and innate immunity, an observation that has been supported by others.…”

Section: Introductionmentioning

confidence: 99%

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge

Elzey

Schmidt

Crist

et al. 2008

Blood

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Collagen exposure in tissue activates platelets, initiates wound healing, and modulates adaptive immunity. In this report, data are presented to demonstrate a requirement for platelet-derived CD154 for both collagen-induced augmentation of T-cell immunity and induction of protective immunity to Listeria challenge. Specifically, we demonstrate that Ad5 encoding the membrane-bound form of ovalbumin (Ad5-mOVA) delivered in collagen induces higher ovalbumin-specific cytotoxic T lymphocyte (CTL) activity in a dose-dependent manner compared with Ad5-mOVA delivered in PBS. Increased CTL activity was dependent on the ability of platelets to respond to collagen and to express CD154. Furthermore, mice immunized with low-dose Ad5-mOVA in collagen were able to control a challenge of Listeria monocytogenes recombinant for ovalbumin expression (Lm-OVA), whereas mice immunized with low-dose Ad5-mOVA in PBS were not. These data indicate that in a physiologic setting that mimics wounding, platelets perform a sentinel function when antigen dose is too low to provoke an efficient immune response, and can enhance the generation of antigen-specific CD8 T cells that are functionally relevant to the host. IntroductionBecause pathogens are capable of logarithmic expansion upon host infection, it is critical that both innate and adaptive immunity are initiated without delay to ensure survival. An effective adaptive response is dependent upon efficient activation of innate immunity since antigen presenting cells (APCs) that are not fully activated are poor stimulators of T-or B-cell responses. [1][2][3] However, the initial infection usually involves entry of only a few microbes resulting in a very low antigen dose unlikely to provoke a prompt immune response. To compensate, the immune system has been designed with important activating early signaling components such as the Toll-like receptor (TLR) family, and costimulatory molecules such as CD40 ligand (CD40L, CD154), which help lower the threshold for cellular activation. 4,5 CD154 is a molecule critical to adaptive immunity. It is required for T-dependent humoral responses including affinity maturation, somatic hypermutation, germinal center (GC) formation, and B-cell memory. 6 In addition, there is a role in some models for CD154 in generation of normal CD8 T-cell memory and cross-presentation of class I-restricted antigen. [7][8][9][10][11][12][13] Until recently, functionally relevant expression of CD154 was thought to be restricted to CD4 T cells where its purpose in cellular immunity is to stimulate APCs that in turn potently activate T cells 2 ; however, functional CD154, which was able to generate an inflammatory response from endothelial cells, has also been reported on platelets. 14 The role platelets can play in antimicrobial immunity is well documented. They are activated by and able to engulf bacteria and viruses, release antimicrobial and antifungal proteins, release reactive oxygen species, express TLR, protect against helminth infections, and play a role in modulating ...

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Section: Introductionmentioning

confidence: 99%

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge

Elzey

Schmidt

Crist

et al. 2008

Blood

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“…Engagement of CD40 by its ligand CD154 plays a central role in mediating the interaction between antigen-presenting cells (APCs) and lymphocytes. 5 Particularly, CD154 derived from activated platelets is involved in multiple immune processes, including endothelial cell reactions, 6 germinal center formation, 7 T-helper cell priming 8,9 and cytotoxic T-cell activation. 10,11 However, the detailed mechanism how platelet CD154 influences the development of different T-cell subsets and consequently shapes the outcome of adaptive immune responses remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Platelets promote allergic asthma through the expression of CD154

et al. 2014

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Platelet activation is associated with multiple immune responses and the pathogenesis of various immune-related diseases. However, the exact role and the underlying mechanism of platelets in the progression of allergic asthma remain largely unclear. In this study, we demonstrate that during antigen sensitization, platelets can be activated by ovalbumin (OVA) aerosol via the upregulation of CD154 (CD40L) expression. Platelet transfer promoted allergic asthma progression by inducing more severe leukocyte infiltration and lung inflammation, elevated IgE production and strengthened T helper 2 (Th2) responses in asthma-induced mice. Accordingly, platelet depletion compromised allergic asthma progression. Cd154-deficient platelets failed to promote asthma development, indicating the requirement of CD154 for platelets to promote asthma progression. The mechanistic study showed that platelets inhibited the induction of Foxp3 1 regulatory T cells both in vivo and in vitro at least partially through CD154, providing an explanation for the increase of Th2 responses by platelet transfer. Our study reveals the previously unknown role of platelet CD154 in the promotion of asthma progression by polarizing Th2 responses and inhibiting regulatory T-cell generation and thus provides a potential clue for allergic disease interventions.

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“…Platelets activate TGFβ by binding the TGFβ‐docking receptor, GARP 80. Platelets activate B cells through CD145‐CD40 interactions and thereby increase production of antibodies 81, 82, 83. Thus, platelets have a complex mechanism of regulating immunity vs. tolerance.…”

Section: Immune System and Its Complexitymentioning

confidence: 99%

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

Rahman

Tiwari

Narula

et al. 2018

CPT Pharmacom & Syst Pharma

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The human adaptive immune system is a very complex network of different types of cells, cytokines, and signaling molecules. This complex network makes it difficult to understand the system level regulations. To properly explain the immune system, it is necessary to explicitly investigate the presence of different feedback and feedforward loops (FFLs) and their crosstalks. Considering that these loops increase the complexity of the system, the mathematical modeling has been proved to be an important tool to explain such complex biological systems. This review focuses on these regulatory loops and discusses their importance on systems modeling of the immune system.

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Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation

Cited by 92 publications

References 26 publications

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge

Platelets promote allergic asthma through the expression of CD154

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

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