T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions

Abstract

Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.

Complement Regulates CD4 T-Cell Help to CD8 T Cells Required for Murine Allograft Rejection

“…The findings in this study indicate that one mechanism through which CD4 cells "license" APCs 8,9 to activate CD8 ϩ T cells is through heightened APC production of C3a/C5a. In vitro, cognate CD4/APC interactions induced C3a/C5a release through a CD40/CD154-dependent mechanism.…”

“…6 The current concept about how CD4 cells provide help to alloreactive CD8 cells is that during cognate CD4 ϩ T-cell/ antigen-presenting cell (APC) interactions, CD154 expressed on CD4 ϩ T cells transmits activating signals to APCs through ligation of APC CD40. [7][8][9] This, in turn, upregulates APC costimulatory molecule (CD80/86) and major histocompatibility complex expression and induces pro-inflammatory cytokines (eg, IL-12), 10 which promote CD8 ϩ T-cell activation, expansion, differentiation, and survival. These concepts are supported by findings in murine transplant experiments that survival of allogeneic heart grafts in CD40 Ϫ/Ϫ recipients is markedly prolonged 11,12 and that cross-linking CD40 in CD4-deficient mice reconstitutes CD8-mediated allograft injury.…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…DC licensing by T helper cells is a well-accepted phenomenon that is crucial for effective CD81 T cell immunity (52,53). DC conditioning requires cognate interaction between CD41 T cells and DCs, is dependent on costimulatory signals, and is crucial for both effector and memory CD81 T cell responses (52,54). In our system, this could be due to either inhibition of secondary costimulatory pathways, such as CD40/CD40L, or inhibition of T cell effector cytokine production.…”

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

“…CD11c 1 DCs are specialized APCs with the highest efficacy to initiate primary immune responses by activating T lymphocytes [10]. However, DC maturation and activation is an essential step for the efficient priming of T lymphocytes [11]. Proinflammatory cytokines are released by activated DCs [12]; co-stimulatory molecules, MHC molecules and adhesion molecules are upregulated, thus inducing a mature state [13,14].…”