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18

Regulatory Immune Cells

James B. Wing, Shimon Sakaguchi

The normal mammalian immune system protects the individual encounter with self antigens, termed peripheral tolerance. For T
from a myriad of potentially pathogenic microorganisms. cells, central tolerance is established in the thymus, where many
However, the immune system must also be tightly regulated to potentially dangerous lymphocytes carrying high-affinity T-cell
prevent it from attacking self-constituents and thus causing receptors (TCRs) for self antigens are deleted via negative selection
autoimmunity. This is partly achieved through central tolerance during development. This results in the generation of a peripheral
and the deletion of T cells that recognize self antigens in the T-cell repertoire that is largely self-tolerant. However, there is
thymus. However, this process is incomplete; that is, some self- abundant evidence that some autoreactive T cells escape thymic
reactive T cells are present in the periphery of healthy individuals deletion, and potentially pathogenic self-reactive T cells are,
and are capable of causing autoimmunity. This creates a need indeed, present in most individuals. Nevertheless, autoimmune
for peripheral tolerance mechanisms that control the action of diseases only occur infrequently, indicating that autoreactive T
such self-reactive cells. cells are somehow controlled in the periphery. Such peripheral
The mechanisms that suppress harmful immune responses mechanisms of self-tolerance include further deletion of self-
are of interest to both basic and clinical immunologists, as the reactive T cells, seclusion of self antigen from T lymphocytes,
failure of protective immunity can lead to increased susceptibility low TCR affinity or lack of costimulation in antigen recognition
to infectious diseases, and loss of self-tolerance may trigger an (clonal ignorance), inactivation of autoreactive T lymphocytes
autoimmune disorder. Furthermore, it is often clinically desirable upon encounter with antigen without costimulation (clonal
to enhance an immune response to certain self (or quasi-self) anergy), and active suppression of self-reactive lymphocytes by
antigens, such as tumor antigens, or to induce immune suppres- other lymphocytes (peripheral suppression). 1
sion for the purpose of facilitating organ transplant acceptance. There are various mechanisms of peripheral self-tolerance,
Elucidation of the mechanisms responsible for immune regulation and this chapter deals with peripheral suppression mediated
and maintenance of self-tolerance is, therefore, one of the primary by regulatory T cells (Tregs) and other suppressive non–T cells.
goals of current medical immunology. Several types of T cells with regulatory activity have been
described, including subpopulations of γδ T cells, natural killer
T cells (NKT cells), and CD8 and CD4 T cells (Table 18.1; Fig.
KEY CONCEPTS 18.1). Some of these Tregs are constitutively produced as a separate
Immunological Self-Tolerance lineage in the immune system, whereas others are induced from
naïve T cells as a product of a particular mode of antigen stimula-
Immunological self-tolerance is actively acquired and maintained throughout tion in a particular cytokine milieu. Although it remains to be
life by a series of mechanisms that cooperatively and complementary determined how each cell population is functionally stable and
operate to prevent the maturation and activation of potentially self-reactive physiologically important, this abundance and apparent redun-
lymphocytes.
The mechanisms include: dancy of Treg populations may not be surprising when one
• Clonal deletion considers how essential it is to maintain immune homeostasis
• Clonal anergy and self-tolerance.
• Clonal ignorance This chapter focuses on CD4 Tregs; in particular thymically
• Dominant suppression produced Tregs (tTregs) that specifically express the transcription
factor Foxp3 and maintain high expression of the interleukin-2
+
+
+
(IL-2) receptor α chain, CD25. Foxp3 CD25 CD4 Tregs have
One key feature of the adaptive immune response is that once been the subject of the majority of recent Treg studies and may
triggered, it shows essentially the same effector activity, whether have the broadest implication to our understanding of the
the target antigen is a microbe or a self antigen, leading to mechanism of various immunological disorders. Loss of function
elimination of the microbe or destruction of self-tissue. To prevent or numerical deficiency of tTreg function or number can be a
self-destructive immune responses while allowing protective primary cause of autoimmune disease, allergy, and inflammatory
immune responses to nonself antigens, the mammalian immune disorders, such as inflammatory bowel disease (IBD) in humans.
system has evolved various regulatory contrivances that inhibit Conversely, since these cells can prevent targeting of tumor tissues
the initial generation of potentially harmful self-reactive T and by conventional CD4 and CD8 T cells, inactivating them is a
B lymphocytes, termed central tolerance, or, after lymphocyte key goal in cancer immunotherapy. Because of their natural
generation, downregulate cellular activation and expansion upon presence in the immune system, they are also a good target for

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