Specificity, restriction and effector mechanisms of immunoregulatory CD8 T cells

Abstract

Historically, CD8 T cells have been divided into cytotoxic T cells and suppressor T cells. Cytotoxic CD8 T cells have been regarded as a homogeneous population of CD4-dependent cells producing a limited number of cytokines – namely interferon (IFN-γ), tumour necrosis factor (TNF-α) and lymphotoxin. Their function was thought to be restricted to defence against viral infections and intracellular pathogens. CD8 suppressor T cells were considered a functionally distinct population of CD8 T cells, which switch off established immune responses or maintain tolerance to particular antigens.1–4 The idea of suppressor T cells first arose in the late 60s and early 70s, when early work of Gershon and colleagues showed that adoptive transfer of T cells from animals tolerant to a particular antigen could specifically suppress antibody production (against that particular antigen) in the recipient animals.5,6 The advances in immunology during the 1970s led to the idea that distinct T cell functions were mediated by distinct subsets of T cells, expressing different cell surface molecules. These findings were further extended to other species, and it was subsequently proposed that cytotoxic and suppressor populations belonged to the CD8 T-cell subset.7–10 In the early studies in both mice and human models suppression was shown to require interaction between CD8 and CD4 T cells. It was proposed that activated CD4 T cells were required for the induction of the CD8 suppressor cells11,12 which then mediate suppression by inhibiting functions of the inducing CD4 T-cell population. These experiments led to models in which very complex cellular circuits were proposed13–16 involving a confusing array of suppressor cells, factors and mechanisms. To this day the existence of these putative antigen (Ag)-specific suppressive factors has not been resolved leading to widespread dismissal of the existence of suppressor cells.17 However, CD8 T-cell-mediated suppression has been clearly demonstrated in a number of systems including: antibody responses to soluble and cellular antigens,18–20 responses to superantigens,21,22 graft-versus-host disease (GVHD),23 allograft rejection,24 asthma (virus induced)25 and in oral tolerance.26,27 More recently, a number of groups have demonstrated that human, murine and rat CD8 T cells have the potential to produce a much wider array of cytokines than was initially thought. Moreover, CD8 T cells appear to differentiate in a polarized fashion and can be divided into subsets analogous to those described for CD4 T cells. These subsets were termed type 1 or Tc1 and type 2 or Tc2.28,29 However, while in the CD4 cells, different cytokine profiles were closely associated with specific functions, i.e. T helper type 1 (Th1) cells were inflammatory T cells, while T helper type 2 (Th2) cells were helpers for antibody production, a correlation between cytokine profile and function has yet to be clearly defined for CD8 T cells. Furthermore it is difficult to associate the newly described CD8 T-cell subsets with phenomena of immune suppression. However, as some CD8 T cells produce potent immunoregulatory cytokines such as interleukin-4 (IL-4),30 IL-1031 and transforming growth factor-β (TGF-β),32 it is likely they may play a role in immune regulation including suppression. In addition, more and more evidence has emerged indicating that CD8 T cells have the capacity to regulate both the induction and effector phases of the immune response through their secreted products or through direct interaction with other cells. Here, we review evidence, old and new, for the capacity of CD8 T cells to influence the outcome of numerous immune responses.