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Abstract
CD40L is essential for the development of adaptive immune responses. It is generally thought that CD40L expression in CD4+ T cells is regulated transcriptionally and made from new mRNA following antigen recognition. However, imaging studies show that the majority of cognate interactions between effector CD4+ T cells and APCs in vivo are too short to allow de novo CD40L synthesis. We previously showed that Th1 effector and memory cells store preformed CD40L (pCD40L) in lysosomal compartments and mobilize it onto the plasma membrane immediately after antigenic stimulation, suggesting that primed CD4+ T cells may use pCD40L to activate APCs during brief encounters. Indeed, our recent study showed that pCD40L is sufficient to mediate selective activation of cognate B cells and trigger DC activation in vitro. In this study, we show that pCD40L is present in Th1 and follicular helper T cells developed during infection with lymphocytic choriomeningitis virus, Th2 cells in the airway of asthmatic mice, and Th17 cells from the CNS of animals with experimental autoimmune encephalitis (EAE). pCD40L is nearly absent in both natural and induced Treg cells, even in the presence of intense inflammation such as occurs in EAE. We also found pCD40L expression in CD4 single positive thymocytes and invariant NKT cells. Together, these results suggest that pCD40L may function in T cell development as well as an unexpectedly broad spectrum of innate and adaptive immune responses, while its expression in Treg cells is repressed to avoid compromising their suppressive activity.
Highlights
T cell help for APCs is essential for adaptive immune responses [1,2]
A contribution of new CD40L protein expression from stable pre-existing CD40L mRNA cannot be fully excluded by limiting the assay to 30 minutes [38], we showed in a previous report with T effectors that complete inhibition of protein synthesis did not diminish surface expression of CD40L following 30 minutes of stimulation [17]
As a membrane-bound cytokine, CD40L is designed for delivery by cell contact, and is necessary for cognate help for B cells and licensing of dendritic cells (DCs) [1,2], so regulated surface expression of preformed CD40L (pCD40L) could explain antigen-specific activation of APC in brief interactions with CD4+ T cells in vivo. pCD40L has been reported in CD4+ T cells [16,17,24,25,26,27,28], but it is not yet known which functions of CD40L require de novo CD40L synthesis and which can be supplied by pCD40L
Summary
T cell help for APCs is essential for adaptive immune responses [1,2]. Effector CD4+ T cells deliver help to antigen-specific B cells in an MHC class II-restricted manner [3]. Lack of CD40L expression causes defective humoral and cellular immunity [5]. Dysregulated CD40L expression causes autoimmunity, lymphoma, and premature termination of humoral immunity [6,7,8,9]. A recent clinical trial of recombinant CD40L failed to restore B cell responses whereas it successfully elicited Th1 responses in patients who harbor mutations in the genes encoding CD40L [10]. A precise understanding of CD40L regulation, including its expression and manner of delivery, could assist in the development of effective vaccines, immunological interventions for inflammatory diseases, and successful treatment of CD40L deficient patients
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