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

Abstract

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 ...

Emerging roles for platelets as immune and inflammatory cells

“…106 Platelet CD40L augments T-cell immunity to viral challenge and is necessary for optimal production of immunoglobulin G by inducing DC maturation and B-cell isotype switching. 107,108 It has also been suggested that when antigen-specific B and T cells are rare, platelets enhance signals needed for adaptive humoral immunity and germinal center formation. 108 We have recently discovered in a mouse cardiac transplant model that platelets have a central role in maintaining CD4…”

Platelets activate a pathogenic response to blood-stage Plasmodium infection but not a protective immune response

“…Indeed, CD40L + WT platelets adoptively transferred to CD40LΚΟ mice activate the protective immune response in virus-or bacteria-infected mice [22][23][24] . However, neither high dose aspirin nor platelet depletion starting at day -1PI affected the primary parasitemia.…”

Nouvelle Cuisine: Platelets Served with Inflammation

“…Platelet-derived CD40L also was shown to enhance CD8 + T cell responses and to promote T cell responses postinfection with Listeria monocytogenes (49,50), thereby bridging the gap between innate and adaptive immunity. Such studies extend platelet function to modulation of innate and adaptive immunity through, for example, release of chemokines, cytokines, and immunomodulatory ligands, including CD40L, and showed that platelets, via CD40L, can induce DC maturation (51).…”