An integrated view of suppressor T cell subsets in immunoregulation

Abstract

The immune system evolved to protect organisms from a virtually infinite variety of disease-causing agents but to avoid harmful responses to self. Because immune protective mechanisms include the elaboration of potent inflammatory molecules, antibodies, and killer cell activation--which together can not only destroy invading microorganisms, pathogenic autoreactive cells, and tumors, but also mortally injure normal cells--the immune system is inherently a "double-edged sword" and must be tightly regulated. Immune response regulation includes homeostatic mechanisms intrinsic to the activation and differentiation of antigen-triggered immunocompetent cells and extrinsic mechanisms mediated by suppressor cells. This review series will focus on recent advances indicating that distinct subsets of regulatory CD4+ and CD8+ T cells as well as NK T cells control the outgrowth of potentially pathogenic antigen-reactive T cells and will highlight the evidence that these suppressor T cells may play potentially important clinical roles in preventing and treating immune-mediated disease. Here we provide a historical overview of suppressor cells and the experimental basis for the existence of functionally and phenotypically distinct suppressor subsets. Finally, we will speculate on how the distinct suppressor cell subsets may function in concert to regulate immune responses.

Figure 1

Homeostatic control of the outgrowth of antigen-activated CD4⁺ T cells. Control of the peripheral immunity is accomplished by mechanisms intrinsic to antigen activation of CD4⁺ T cells; including apoptosis, induction of anergy, and differentiation into Th subsets that are independent of other types of regulatory cells. In addition, superimposed on these intrinsic mechanisms are control mechanisms mediated by distinct subsets of NKT, CD4⁺, and CD8⁺ regulatory (suppressor) T cells.

Figure 2

Model of cognate interactions in the induction and function of Qa-1–restricted regulatory CD8⁺ T cells. (A) Initial activation of CD4⁺ T cell TCRs with peptide–MHC complexes induces the expression of Qa-1 bound with a variety of self-peptides on the surface of the CD4⁺ T cells. (B) Anti–Qa-1–self-peptide CD8⁺ precursor T cells are activated by Qa-1–expressing CD4⁺ T cells. The Qa-1–restricted CD8⁺ Tregs selectively downregulate certain but not all antigen-activated CD4⁺ T cells based on the specific recognition of Qa-1–self-peptide complexes expressed on certain CD4⁺ T cells by TCR αβ on the CD8⁺ T cells. In this regard, we have demonstrated in the EAE model that self-reactive CD4⁺ T cells, which are selectively downregulated by the CD8⁺ T cells, are enriched in potentially pathogenic self-reactive T cell clones (9).

Figure 3

Tregs control the peripheral induction and clonal outgrowth of antigen-reactive T cells. This illustration shows various pathways of immunoregulation mediated by suppressor subsets of NKT, CD4⁺, and CD8⁺ T cell subsets. Each of the regulatory T cell subsets expresses distinct receptors, employs different effector mechanisms, and functions predominately at different stages during the course of the peripheral immune response. The NKT and CD4⁺CD25⁺ regulatory cells are “natural suppressor cells”; they are present prior to antigen activation and primarily function during the early “innate” and/or primary adaptive immune responses. In contrast, the CD8⁺ regulatory cells are induced to differentiate into suppressor effector cells during the primary immune response, and they function as effector-suppressor cells predominately during the secondary and memory phases of immunity.