anergy or receptor editing to eliminate autoreactive αβT cells in the thymus [8] and autoreactive B cells in the bone marrow [9]. The tolerogenic mechanisms for different immune cell lineages show similarities and differences.
Central T‐cell Tolerance
T cells with high affinity TCRs for self HLA–self peptide complexes are eliminated in the thymus by clonal deletion [8]. This process of negative selection favors the survival of T cells with TCRs that exhibit either no or very low affinity for self‐HLA–autoantigen peptide complexes. Among the natural (n) αβT cells selected in the thymus are subsets of CD4 T cells, including nTregs, NKT cells, and IL‐17‐secreting nTh17 cells. Given the dichotomous functions of nTregs and nTh17 cells to suppress versus augment inflammatory pathology, thymic regulation of the balance of these subsets is an important determinant of the risk for autoimmunity. Overall, more than 95% of T cells generated in the thymus undergo deletion because of excessive self‐reactivity, which underscores the high frequency of autoreactive TCRs among T cells.
Negative selection of autoreactive T cells by is mediated by the coordinated display of self‐HLA molecules containing self‐peptides generated by expression of genes controlled by the autoimmune regulator (AIRE) transcription factor. In addition to DCs, medullary thymic epithelial cells (mTECs) selectively express AIRE, which drives tissue‐specific self‐antigen expression required for deletion of T cells with TCRs that react strongly with autoantigens. In addition, thymic B class switching also promotes central tolerance through negative selection of CD4 T cells. The importance of AIRE in central tolerance is underscored by the consequences of genetic AIRE deficiency in humans, which results in an autoimmune disease characterized by autoimmune polyendocrine syndrome type 1 (APS‐1) [1]. AIRE is also involved in peripheral T‐cell tolerance and is expressed in peripheral lymph nodes and the spleen where it mediates elimination of autoreactive extrathymic T cells.
Thymic editing of TCRs plays a seminal role in the genesis of the TCR repertoire and is mediated by recombination activating gene (RAG)‐1 and RAG‐2 proteins. After RAG proteins are induced during T‐cell development, they cause TCR β‐chain rearrangement and expression of prefabricated TCR α‐chains to form pre‐TCRs. A subsequent round of RAG protein induction transcribes rearranged TCR α‐chains that displace prefabricated α‐chains. Yet another round of induction of RAG proteins finalizes rearrangements of α‐chains, forming functional α/β TCRs to undergo thymic selection. This thymic process of TCR editing has a counterpart in the periphery, referred to as TCR revision, which can generate an unlimited array of antigen‐specific TCRs, overcoming the effects of thymic TCR selection. These newly generated TCRs likely contribute to peripheral creation and evolution of autoreactive T cells (discussed later).
Central B‐cell Tolerance
B cells develop tolerance to self‐antigens in the bone marrow by both B‐cell receptor (BCR) editing and clonal deletion of autoreactive B cells [9]. BCR editing results from the induction of VDJ recombinase and rearrangements which lead to production of new immunoglobulin‐edited light chains that modify the specificity of BCRs to prevent recognition of autoantigens.
Peripheral Tolerance
Central immunologic tolerance for both T and B cells occurs in the early developmental stages of both lineages. Additional mechanisms are required, however, to achieve tolerance to self‐antigens that are not expressed during fetal or neonatal life or are expressed exclusively in peripheral non‐lymphoid organs [10].
T‐ and B‐cell Clonal Anergy
Clonal anergy is a major mechanism in the generation and maintenance of peripheral tolerance to self‐antigens (Figure 2.2) [10]. Autoreactive T‐cell clones not deleted in the thymus or the peripheral lymphoid tissues may become anergic to autoantigens if TCR activation occurs in the absence of obligatory costimulation. Lack of costimulation results in inadequate secretion of IL‐2 and growth factors required for T‐cell clonal proliferation and maturation of effector functions. Without costimulation, autoantigen‐specific T cells cease to differentiate and fail to respond if reexposed to autoantigen. Anergic B cells have reduced surface IgM, impaired signal transduction and short lifespans, and exhibit anergy to autoantigen reexposure.
T‐cell Mediated Immune Regulation
A subclass of CD4 T cells referred to as Tregs are essential for peripheral tolerance and maintenance of immune homeostasis (Figure 2.2) [11]. Tregs mediate immune tolerance by functionally suppressing all activated CD4 T‐cell subsets and CD8 CTLs. Thus, reductions in the numbers or functional capacity of Tregs can facilitate autoimmunity and autoimmune diseases. Phenotypically, Tregs are CD4, CD25, forkhead box P3 (FoxP3) T cells. FoxP3 is the key regulator of Treg function, as shown by monogenic deficiency in FOXP3 that results in immunodysregulation, polyendocrinopathy and enteropathy X‐linked (IPEX) syndrome [1]. FoxP3‐deficient mice also develop autoimmune diseases, which can be prevented by adoptive transfer of CD4, CD25, FoxP3 Tregs. FoxP3 Tregs secrete immunoregulatory and immunosuppressive cytokines, including, IL‐9, IL‐35, IL‐10 and transforming growth factor (TGF)‐β. These cytokines immunosuppress activated CD4 and CD8 T cells and promote T‐cell anergy by downregulating APC expression of costimulatory CD80 and CD86. In addition, Treg upregulation of intracellular cyclic AMP directly inhibits cell proliferation and reduces production of IL‐2 required for T‐cell proliferation.
Natural and Inducible T Regulatory Cells
Tregs are classified as natural Tregs (nTregs) or inducible Tregs (iTregs) [11]. nTregs are produced in the thymus and represent 5–10% of the total CD4 T‐cell population. Despite having a relatively high affinity for autoantigens, nTregs escape clonal deletion in the thymus. In the periphery, nTregs act as autoantigen‐specific sentinels within the lymph nodes and spleen to maintain peripheral tolerance. They do so by inhibiting autoantigen activation of T cells by APCs, causing direct cytotoxicity of autoantigen‐activated T cells and secreting anti‐inflammatory cytokines IL‐10 and TGF‐β.
iTregs are a subset of CD4 T cells activated in the periphery (Figure 2.2). When naive CD4 T cells (CD4 Th0 cells) are activated in the presence of IL‐10, IL‐4 and TGF‐β, they differentiate into antigen‐specific CD4, CD25, FoxP3 iTregs. Both foreign antigens and autoantigens can generate antigen‐specific iTregs, conferring immunoregulatory importance in both normal immunity and autoimmunity. iTregs suppress effector CD4 T‐cell subsets and cytotoxic CD8 T cells by secreting immunosuppressive IL‐10 and TGF‐β, inducing cell cycle arrest and effector T‐cell apoptosis. In addition, iTregs block the costimulation and maturation of DCs. Among iTregs (Figure 2.2), the T regulatory 1 (Tr1) subclass exclusively secretes IL‐10 but does not express FoxP3. In contrast, the T helper 3 (Th3) subclass exclusively secretes TGF‐β.
Peripheral B‐cell Regulatory Mechanisms
Activated B regulatory cells (Bregs) also secrete immunosuppressive cytokines IL‐10, IL‐35 and TGF‐β. IL‐10 and IL‐35 render CD4 Th1 and Th17 cells incapable of mediating immunopathology or producing proinflammatory cytokines [12]. In contrast, Breg secretion of TGF‐β promotes antigen‐activated CD4 T‐cell differentiation into iTregs (Figure 2.2), secreting IL‐10 that inhibits TNF‐α production. Additional mechanisms also contribute to B‐cell immunoregulation. Secreted IgM induces anti‐inflammatory apoptotic bodies to reduce proinflammatory cytokines. Contact between B and CD4 T cells reduces CD4 T‐cell proliferation and secretion of