Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press T-Cell Tolerance: Central and Peripheral Yan Xing and Kristin A. Hogquist Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455 Correspondence: [email protected] Somatic recombination of TCR genes in immature thymocytes results in some cellswith useful TCR specificities, but also many with useless or potentially self-reactive specificities. Thus thymic selection mechanisms operate to shape the T-cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide–MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect. Clonal deletion and clonal diversion (Treg differentiation) are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient, they fail to control self-reactivity in all circumstances. Thus, peripheral toler- ance processes exist wherein self-reactive T cells become functionally unresponsive (anergy) or are deleted after encountering self-antigens outside of the thymus. Recent advances in mechanistic studies of central and peripheral T-celltolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome. cells recognize pathogen fragments in the However, not all antigens that T cells need to be Tcontext of surface MHC molecules on host tolerant of are expressed in the thymus, and thus cells. As such, they have the potential to do enor- central tolerance mechanisms alone are insuffi- mous damage to healthy tissue when they are cient. Fortunately, additional tolerance mech- not appropriately directed, that is, when they anisms exist that restrain the numbers and or respond to self-antigens as opposed to foreign function of T cells that are reactive to develop- antigens. T lymphocyte tolerance is particularly mental or food antigens, which are not thymi- important, because it impacts B-cell tolerance as cally expressed. These mechanisms act on ma- well, through the requirement of T cell help in ture circulating T cells and are referred to as antibody responses. Thus, failure of T-cell tol- “peripheral tolerance.” erance can lead to many different autoimmune diseases. The tolerance of T cells begins as soon CENTRAL TOLERANCE as a T-cell receptor is formed and expressed on the cell surface of a T-cell progenitor in the thy- T lymphocytes arise from circulating bone-mar- mus. Tolerance mechanisms that operate in the row-derived progenitors that home to the thy- thymus before the maturation and circulation mus. After T lineage commitment and expan- of T cells are referred to as “central tolerance.” sion, T-cell receptor (TCR) gene rearrangement Editors: Diane J. Mathis and Alexander Y. Rudensky Additional Perspectives on Immune Tolerance available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006957 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a006957 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Y. Xing and K.A. Hogquist ensues and gives rise to either gd or ab progen- dergoing secondary gene rearrangement at the itors at the CD4 and CD8 double-negative (DN) TCRa loci, thereby changing the specificity of stage. A small number of ab committed DN the TCR. This process is known as “receptor cells give rise to a large number of CD4 and editing.” Although examples of receptor editing CD8 double-positive (DP) thymocytes, and so- exist for T cells (Wanget al. 1998; McGargill et al. matic recombination of TCR genes results in 2000, 2002; Buch et al. 2002; Santori et al. 2002), a remarkably broad repertoire of distinct ab it is unclear how prominent this mechanism TCRs with random specificity. The TCR affinity is (Holman et al. 2003), and it will not be dis- for self-peptide–major histocompatibilitycom- cussed further here. Finally, a state of unrespon- plex (MHC) determines a thymocyte’s fate from siveness can be induced in self-reactive thymo- this point forward (Fig. 1). DP thymocytes ex- cytes, called “anergy.” Anergy is likely a more pressing TCRs that do not bind self-peptide– prominent tolerance mechanism that operates MHC complexes die by neglect. Those with a in the periphery and is discussed further in low affinity for self-peptide–major histocom- that section. These four processes—clonal dele- patibility complex MHC complexes differenti- tion, clonal diversion, receptor editing, and an- ate to CD4 or CD8 single-positive (SP) thymo- ergy—are the major mechanisms that limit the cytes—so-called positive selection. However, self-reactivity of the T-cell repertoire and are those with high-affinity TCR for self-peptide– crucial for immune health. MHC complexes represent a potential threat to the health of the animal, and various mecha- CLONAL DELETION nisms operate to ensure tolerance to self, includ- ing clonal deletion, clonal diversion, receptor In this section, we discuss several fundamental editing, and anergy. questions of clonal deletion, such as: At which In the thymus, one of the main mechanisms stages of development do thymocytes undergo of T-cell tolerance is “clonal deletion,” although deletion? Where does it occur anatomically? the selection of regulatory T cells (“clonal diver- What cell types induce apoptosis? What is the sion”) is also important and is of enormous in- molecular mechanism? terest (see Benoist 2012). Thymocytes express- The thymus is composed of two major an- ing high-affinity TCR for self-peptide–MHC atomical areas—an outer region known as the can avoid the deletion or diversion fates via un- cortex, which contains DN and DP thymocytes, Death Cells Clonal by Positive deletion neglect selection Treg TCR affinity Figure 1. A model for the relationship between developmental outcome and TCR affinity for self-peptide– MHC. Cells with TCR that have a low affinity for self die by neglect. Those with an intermediate affinity are positively selected. High-affinity self-reactive clones can die via clonal deletion, and the threshold between positive and negative selection is hypothesized to be steep. Regulatory T cells (Treg) (yellow) have more highly self-reactive TCRs than most conventional T cells (purple). Some Tregs may have very highly self-reactive TCRs and are rescued from deletion via cytokine signaling or by virtue of having a second TCR (dotted line). 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a006957 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press T-Cell Tolerance and an inner region known as the medulla, tified by the observation that superantigens are which contains SP thymocytes (Fig. 2). Positive primarily expressed in the medulla, which is the selection of thymocytes occurs in the cortex. site where SP thymocytes reside. Likewise, tis- However, whether or not clonal deletion occurs sue-specific antigens are often expressed exclu- in the cortex has been controversial. For exam- sively in the medulla (see below for further dis- ple, superantigen studies have suggested that cussion). In contrast, in TCR transgenic models deletion occurs at the SP stage (Kappler et al. where the TCR is specific for ubiquitous self- 1987) (in the thymic medulla), whereas exam- antigens, deletion occurs at the DN-to-DP tran- ination of TCR transgenics and endogenous sition. However, in transgenic models, thymo- self-antigens had suggested that deletion occurs cytes express both TCRb and TCRa chains early at the transition from DN to DP (Kisielow et al. at the DN stage and undergo negative selection 1988; Sha et al. 1988) (in the thymic cortex). prematurely (Baldwin et al. 2005; Egawa et al. This apparent discrepancy can be partially rec- 2008). What is clear is that the nature of TCR Positive selection, neglect, and clonal deletion Clonal deletion and Treg differentiation Apoptosis Cortex Medulla (neglect) Treg SP Apoptosis DP (deletion) Apoptosis (deletion) DC DC cTEC mTEC CD28 CD4 DP SP CD4 or CD8 B7 TCR or CD8 CD40L p-MHC TCR RANKL β5i p-MHC LT CD40 Ctss RANK β5t AIRE TSSP LT-βR TSAs B7 Ctsl B7 p-MHC p-MHC CD40 CD40 DC cTEC DC mTEC Figure 2. Cell types in central tolerance. (Top) T cells are positively selected in the thymic cortex. Negative selection via clonal deletion can also occur in the cortex, but occurs frequently in the medulla. The thymic medulla is also the site for Treg differentiation. (Bottom) Cortical thymic epithelial cells (cTECs) express several unique genes that relate to proteolysis (cathepsin L, Ctsl; thymus-specific serine protease, TSSP; and b-5t proteasome subunit, b5t), which are essential for positive selection. Tissue-specific antigens (TSAs) can be directly presented by medullary thymic epithelial cells (mTECs) or cross-presented by DC (dotted line with arrow). RANKL, CD40L, and lymphotoxin (LT) expressed by SP thymocytes interact with their receptors on mTEC to promote the development of mTEC. Cite this article as Cold Spring Harb Perspect Biol 2012;4:a006957 3 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Y. Xing and K.A. Hogquist and self-antigen expression can dramatically trophy syndrome (APECED) (Anderson and impact the