Immune system and related disorders

T cells

T cells begin life in the bone marrow and complete their maturation in the thymus , a lymphoid organ located in the anterior mediastinum ( Fig. 11.2 ). Immature CD7/TdT + CD3 − precursor T cells migrate from the bone marrow to the outer thymic cortex ( Fig. 11.3 ). At this stage, the precursor T cells ( cortical thymocytes ) undergo rearrangement of the βTCR , γTCR , and δTCR genes. In most cases (95%), beta-chain rearrangement occurs first and leads to expression of a heterodimeric pre-TCR composed of beta chain complexed with an invariant pre-alpha chain. This is followed by alpha chain rearrangement and suppression of gamma and delta chain rearrangement. Expression of the mature heterodimeric alpha/beta TCR ( TCRαβ ), along with accessory molecules CD3, CD4, and CD8, allows interaction of cortical thymocytes with common self-antigens expressed by endoderm-derived cortical thymic epithelial cells and marrow-derived thymic dendritic cells . Both thymic cell types present self-antigens in association with self- MHC (major histocompatibility complex) protein. The terms MHC and HLA are often used interchangeably. However, strictly speaking, MHC (major histocompatibility complex) refers to the gene complex, and HLA (human leukocyte antigen) refers to the proteins encoded by MHC genes. Whereas cortical T cells that bind to these specialized antigen-presenting cells (APCs) via their TCR complexes are positively selected for further development in the thymic medulla , T cells that fail to bind to self-antigen undergo apoptosis (cell death). T cells with no interaction with self-antigen are deleted because they are unlikely to recognize foreign antigen bound to self-MHC (“altered self”).

Positively selected cortical T cells that bind to self-antigen in association with HLA class I lose expression of CD4 to become mature CD8 + T cells, and positively selected T cells that bind to self-antigen in association with HLA class II lose expression of CD8 to become mature CD4 + T cells. Whereas CD4 stabilizes the TCR complex by binding to the invariant backbone of the HLA class II molecule, CD8 stabilizes the invariant backbone of the HLA class I molecule. Both subsets (CD4+ and CD8+) of positively selected cortical T cells migrate into the thymic medulla.

Within the medulla, the developing T cells encounter a greatly expanded universe of more restricted, often organ-specific self-antigens expressed by medullary thymic epithelial cells (MTEC) and medullary thymic dendritic cells ( Fig. 11.4 ). Expression of organ-specific antigens by MTEC is mediated by the transcription factor autoimmune regulator . Thymic T cells with receptors that bind weakly to self-antigen proliferate through the process of positive selection , and thymic T cells that express receptors with no affinity for self-antigen die of neglect. In a process termed negative selection , thymic T cells that bind avidly to self-antigens undergo apoptosis, are rendered anergic (unresponsive) or are converted to FoxP3+ regulatory T (Treg) cells . Treg cells suppress immune responses in an antigen-specific fashion and provide a second line of defense against self-reactive T cells that escape thymic deletion.

The relatively few cortical thymocytes that undergo productive gamma-delta rearrangement (5%) express CD3 but unlike the more common alpha-beta T cells do not express CD4 or CD8. These double-negative gamma-delta T cells respond directly to antigen in an HLA-unrestricted fashion. Gamma-delta T cells express cell surface antigens CD16 (a low-affinity immunoglobulin Fc [fragment crystallizable] receptor) and CD56 (a homophilic adhesion receptor), proteins that are also expressed by NK cells. Many antigens recognized by gamma-delta T cells are unconventional phosphoantigens, endogenous metabolites of cholesterol biosynthesis produced by bacteria. Gamma-delta T cells home primarily to mucocutaneous sites (the skin, genital tract, and gastrointestinal tract), where they serve as first responders to commonly encountered bacteria.

From the thymic medulla, most mature T cells are released into the peripheral circulation and migrate to secondary lymphoid tissues: the lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT) , bronchial-associated lymphoid tissue (BALT) , and so on. After antigen encounter, naïve CD4 + T cells differentiate into Th1, Th2, Th3, Th17, Treg, or Tfh cells. Antigen-activated Th1 cells drive proinflammatory T cell–mediated immune responses by secreting proinflammatory cytokines ( interferon-γ [IFN-γ] and transforming growth factor β [TGF-β]) that induce activation of CD8 + cytotoxic T cells (CTLs) . Antigen-activated Th2 cells , on the other hand, drive antiinflammatory T cell–mediated immune responses by secreting interleukin (IL)-10 and humoral-mediated immune responses by secreting cytokines IL-4, IL-6, and IL-21 that induce B-cell activation and plasma cell maturation. Th3 cells present in gut-associated lymphoid tissues (GALT) contribute to oral tolerance to food antigens by producing antiinflammatory cytokines IL-10 and TGF-β. IL-10 inhibits proinflammatory Th1 responses, and TGF-β favors production of noninflammatory immunoglobulin (Ig) A. By secreting IL-17, proinflammatory Th17 cells recruit neutrophils to sites of infection. Similar to Th3 cells, FoxP3+ Treg cells inhibit T-cell immune responses by inhibiting IL-2–mediated T cell growth factor IL-2 and producing antiinflammatory IL-10 and TGFβ. Follicular T-helper (Tfh) cells are specialized memory T cells that provide growth signals to germinal center B cells. Tfh home to CXCL13 + lymphoid follicles via receptor–ligand interaction between the chemokine receptor CXCR5, expressed by Tfh, and the chemokine CXCL13, expressed by follicular dendritic cells (FDCs) .

B cells

The earliest identifiable B-cell precursor, the progenitor B cell , is characterized by expression of B cell–specific cell surface proteins CD19 and CD10 and immunoglobulin genes in germline configuration ( Fig. 11.5 ). Expression of the enzymes RAG1, RAG2, and TdT heralds initiation of immunoglobulin heavy chain gene rearrangement. Synthesis of mu heavy chain and marked reduction in RAG and TdT activity define the precursor B-cell stage. At this stage, most mu heavy chain is found in the cytoplasm, with only a small amount expressed on the cell surface in association with an invariant surrogate light chain to form the pre-B cell receptor (pre-BCR) . Signaling through the pre-BCR triggers light chain rearrangement, leading to the next stage of B cell maturation, the immature B cell stage. Immature B cells express cell surface IgM, which associates with the invariant Igαβ heterodimer ( CD79 a/CD79b). B-cell activation induced by antigen cross-linking of IgM is mediated by intracellular signaling through the invariant Igαβ heterodimer. Immature B cells that bind avidly to self-antigen in the bone marrow undergo receptor editing, deletion by apoptosis, or functional inactivation, also known as anergy . If successful, receptor editing , triggered by reactivation of light chain gene rearrangement, leads to the expression of non–self-reactive immunoglobulin. The phenomenon of negative selection of immature B cells in the marrow, somewhat analogous to negative selection of immature T cells in the thymus, is important in deletion of potentially pathogenic self-reactive (autoimmune) B cells from the immature B-cell pool.

Surviving marrow B cells exit the marrow as mature naïve B cells that, through a process of differential mRNA splicing of the primary mu-delta transcript, coexpress both surface IgM and IgD. At this stage, RAG expression is terminated. The function of membrane IgD, although not entirely understood, may be to prevent antigen-induced apoptosis or anergy of naïve B cells by providing T cell co-stimulation by IgD receptor-bearing T-helper cells. Naïve B cells are drawn to lymphoid follicles via interaction between CXCR5 expressed by B cells and CXCL13 released by follicular dendritic cells . Soluble antigen that binds to surface IgM or IgD of naïve antigen-specific B cells is internalized, proteolytically degraded to small peptides, and presented on the B cell surface by HLA class II.

Meanwhile, naïve CD4 + T cells released from the thymus migrate from the blood, through high endothelial venules and into lymph node paracortical T zones, where they encounter soluble antigen presented by interdigitating dendritic cells (IDCs) in association with HLA class II. IL-12 released by activated IDCs also provides an additional T-cell proliferative stimulus.

Antigen-primed B cells migrate from the lymphoid follicle into the paracortical T zone, where they cross-present HLA class II-bound molecules to activated T-helper cells, which then signal the B cells to proliferate and differentiate into extrafollicular B cell blasts in a small region called the primary focus ( Fig. 11.6 ). Although some antigen-activated B cells develop into short-lived IgM-secreting plasma cells (the primary humoral immune response), most B blasts in the primary focus return to the lymphoid follicle to form a prominent secondary focus called the germinal center . With help from Tfh cells and antigen-bearing FDCs, germinal center B cells undergo multiple rounds of proliferation and somatic (Ig variable region) hypermutation. Somatic hypermutation of the immunoglobulin variable region genes is dependent on activity of activation-induced cytidine deaminase , an enzyme that converts deoxycytidine (in DNA) to uracil, which triggers processing by uracil DNA glycosylase (UNG) and endonucleases, leading to error-prone DNA repair and hypermutation. Germinal center B cells that produce antibody of high affinity are positively selected—a process known as affinity maturation —and B cells that fail to develop high-affinity antibody undergo apoptosis. Under the influence of T-helper cells, positively selected IgM- and IgD-positive germinal center B cells undergo heavy chain class switching or isotype switching from IgM/IgD to IgG, IgA, or IgE. Whereas B cells in lymph nodes most often switch to IgG expression, B cells in MALT often switch to IgA production for transport into body secretions. Whereas IgG binding to microbes leads to complement activation and phagocytosis, IgA binding to microbes leads to neutralization. IgE + B cells are most often found in mast cell- and basophil-rich sites such as the dermis. In these sites, allergens that bind to IgE-bearing mast cells and basophils induce degranulation, with release of histamine. Thus, IgE imbues allergic (hypersensitivity) reactions with antigen specificity.

Some germinal center B cells differentiate into long-lived plasma cells, and others differentiate into memory B cells. Long-lived plasma cells migrate to the marrow and spleen, where they secrete low-level antibody for months to years. Memory B cells are quiescent long-lived IgG + B cells that recirculate in lymph node mantle zones, splenic marginal zones, and MALT located in the skin (skin-associated lymphoid tissue [SALT]), lung (BALT), conjunctiva, and gastrointestinal tract (GALT). Memory B cells activated by antigen within germinal centers provide a rapid secondary IgG-predominant immune response to previously encountered antigen.

Control of the secondary humoral immune response is mediated by an antibody feedback mechanism . Antigen–antibody immune complexes that simultaneously bind IgG Fc receptors (e.g., CD32) and surface immunoglobulin block B-cell activation, thus preventing further development of memory and plasma cells.