What is the third signal?
Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) of the body, and as such play a key role in the signaling of T cells for effector responses to antigen. Various co-stimulatory and adhesive interactions between DCs and T cells are able to drive proliferative, proinflammatory cytokine and cytotoxic effector functions of T cells . The effector response made to antigen presented by DCs depends on the co-stimulatory signals delivered to T cells along with the antigen signal presented in the context of MHC molecules . Lafferty's concept of a second or co-stimulatory signal stands as a key model for our understanding of the generation of immunity, and also for our understanding of the basis for peripheral tolerance .
In recent years, through the study of interactions taking place at the immunological synapse, at which T cells are signaled by antigen-bearing APCs, several groups have studied the minimal requirements of CD4+ and CD8+ T cells for these effector functions. Mescher et al., for example, have done so using a simple system of beads conjugated with MHC and antigen – whose density can be varied – (signal 1), and various membrane co-stimulatory molecules (signal 2), such as CD80/86 or CD54 (ICAM-1). In this context, they have shown for CD8+ T cells that signals 1 and 2 are sufficient for proliferation and cytokine production, but that a third signal, IL-12, is required for cytotoxic effector function . The authors indicate that IL-12 is not the only soluble factor which can function as a third signal for CD8+ T cells, but that it can be substituted by other, as yet unknown, factors.
In a recent paper, Mescher et al. extend the concept of the third signal in vivo to show that the presence of signals 1 and 2 but the absence of IL-12 results in peripheral tolerance in the CD8+ T-cell compartment . Thus, CD8+ T cells are able to proliferate and to produce IFN-γ in vivo in the absence of IL-12, but this cytokine production and cytotoxic T-lymphocyte (CTL) activity are limited. The data are consistent with the work of others, showing the important role of IL-12 in driving IFN-γ effector function by T cells . Further upstream, IL-12 production by DCs has been shown to be driven by dual TLR (toll-like receptor) and CD40 signals . In this regard, it is of interest that the minimum required signals for CD154 (CD40L) expression by CD4+ T cells are CD80/86 and CD54, even in the absence of signal 1 .
The signal 3 requirements for CD4+ T cells are less well defined. Indeed it is more difficult to define an effector function beyond cytokine production for CD4+ T cells that is equivalent to the "higher order" effector function represented by CTL activity for CD8+ T cells. This is paradoxical, because higher order consequences of CD4+ T-cell helper function for B cells, CTL activity and memory are driven largely by CD154 as well as other CD40-dependent and -independent co-stimulatory interactions, including OX40, 41BB, ICOS and other members of the B7 family . Nevertheless, using the readout of IFN-γ production by CD4+ T cells as a measure of T helper type 1 (Th1) effector function, Mescher et al. previously suggested that IL-1β could act as a third signal for CD4+ T cells .