Requirement for CD40 Ligand in Costimulation Induction, T Cell Activation, and Experimental Allergic Encephalomyelitis

Abstract

The mechanism of CD40 ligand (CD40L)-mediated in vivo activation of CD4(+) T cells was examined by investigation of the development of experimental allergic encephalomyelitis (EAE) in CD40L-deficient mice that carried a transgenic T cell receptor specific for myelin basic protein. These mice failed to develop EAE after priming with antigen, and CD4(+) T cells remained quiescent and produced no interferon-gamma (IFN-gamma). T cells were primed to make IFN-gamma and induce EAE by providing these mice with B7.1(+) antigen-presenting cells (APCs). Thus, CD40L is required to induce costimulatory activity on APCs for in vivo activation of CD4(+) T cells to produce IFN-gamma and to evoke autoimmunity.

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

“…EAE amelioration by HGF treatment was associated with impaired CD40 expression on DCs, a finding consistent with an important role of DC-expressed CD40 to evoke T cell-activation and CNS autoimmunity (23). Moreover, in agreement with data reporting PD-L1 as necessary for the DC-mediated induction of Treg cells (24) and tolerance, our results indicate that HGF treatment significantly increases PD-L1 expression by DCs.…”

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

“…Studies by Gray et al support these data, in which T cells immunized to KLH in a CD40-deficient host were shown to be incapable of providing T cell help to antigen-specific B cells upon adoptive transfer [30]. Subsequent work by Flavell's group confirmed the need for CD154 expression on CD4 ϩ T cells for their priming to produce effector cytokines [31]. Myelin basic protein (MBP) TCR-Tg mice bred to the CD154-deficient background showed no clinical signs of experimental allergic encephalomyelitis (EAE) and no histological evidence of myelin damage after vaccination with MBP in CFA.…”

“…Furthermore, the inability of CD40-deficient B cells to drive allogeneic T cell proliferation in vitro can be restored if these cells are preactivated with lipopolysaccharide (LPS), and reconstitution of this response can be inhibited by blockade of B7.1 and B7.2 with CTLA4-Ig [43]. In regard to tolerance, it is important to note that the study by Flavell's group also demonstrated that recall proliferative responses by DLN cells after inital antigen exposure in vivo were comparable in wild-type and CD154-deficient MBP TCR-Tg mice [31]. This observation suggests that exposure to antigen in the absence of CD40/CD154 interactions blocks priming (as assessed by IFN-␥ production) but does not induce T cell tolerance in this system.…”

“…Although CFA is a powerful adjuvant and most likely induces significant inflammation at the site of injection [60], it does not appear to allow the immune system to bypass the need for CD40/CD154 interactions for T cell priming in some systems [29]. However, in other systems recall proliferative responses appear normal in the absence of CD40/CD154 costimulation after the administration of antigen with bacterial adjuvant [31,59], suggesting that T cell priming per se is not impaired and that adjuvant can bypass the requirement for this receptor/ligand pair in some cases. During the course of an infection by a viral pathogen such as LCMV, destruction of infected tissues and the production of IFN-␥ as well as other inflammatory cytokines in response to viral replication constitutes a powerful adjuvant to the immune system and is most likely what allows for the expansion and effector maturation of CD4 ϩ and CD8 ϩ T cells in the absence of CD40/CD154 interactions [56][57][58].…”

“…Evidence for a direct relationship between the B7 molecules and impaired T cell responses in the absence of CD40/CD154 interactions has been provided by a number of studies. Flavell and co-workers demonstrated that IFN-␥ production by CD4 ϩ MBP TCR-Tg T cells and EAE susceptibility in CD154-deficient mice could be restored by the adoptive transfer of APCs bearing constitutive levels of B7.1 on their surface [31]. In addition, both helper cytokine and cytotoxic responses against adenovirus in CD154-deficient mice were shown to be reconstituted by the administration of an agonistic anti-CD40 mAb, which correlated with an increase in splenic B7.2 expression in these mice [32].…”