The net result of activation of the humoral (B-cell) and cellular (T-cell) arms of the adaptive immune system by foreign antigen is the elimination of antigen directly by specific effector T cells or in concert with specific antibody.

The expression of adaptive immune cell function is the result of a complex series of immunoregulatory events that occur in phases. Both T and B lymphocytes mediate immune functions, and each of these cell types, when given appropriate signals, passes through stages, from activation and induction through proliferation, differentiation, and ultimately effector functions. The effector function expressed may be at the end point of a response, such as secretion of antibody by a differentiated plasma cell, or it might serve a regulatory function that modulates other functions, such as is seen with CD4 and CD8 T lymphocytes that modulate both differentiation of B cells and activation of CD8 cytotoxic T cells.

TH 1 CD4+ T cells, through elaboration of IFN-γ, have a central role in mediating intracellular killing by a variety of pathogens. TH 1 CD4+ T cells also provide T-cell help for generation of cytotoxic T cells and some types of opsonizing antibody, and they generally respond to antigens that lead to delayed hypersensitivity types of immune responses for many intracellular viruses and bacteria (such as HIV-1 or M. tuberculosis). In contrast, TH 2 cells have a primary role in regulatory humoral immunity and isotype switching. TH 2 cells, through production of IL-4 and IL-10, have a regulatory role in limiting proinflammatory responses mediated by TH 1 cells (Fig. 1). In addition, TH 2 CD4+ T cells provide help to B cells for specific Ig production and respond to antigens that require high antibody levels for foreign antigen elimination (extracellular encapsulated bacteria such as Streptococcus pneumoniae and certain parasite infections). TH 17 cells secrete cytokines IL-17, -22, and -26 and have been shown to play a role in autoimmune inflammatory disorders in addition to defense against extracellular bacteria and fungi, particularly at mucosal surfaces. TH 9 cells are defined by their secretion of IL-9 and have been shown to play a role in atopic disease, inflammatory bowel disease, and antitumor immunity. Moreover, the TFH subset of helper T cells secrete IL-21 and is crucial for providing the necessary signals to B cells in germinal centers to undergo affinity maturation. TFH13 cells secrete IL-4, IL-5, and IL-13 in response to allergens and and have been postulated to mediate anaphylaxis reactions (Fig. 1). In summary, the type of T-cell response generated in an immune response is determined by the microbe PAMPs presented to the DCs, the TLRs on the DCs that become activated, the types of DCs that are activated, and the cytokines that are produced. Commonly, myeloid DCs produce IL-12 and activate TH 1 T-cell responses that result in IFN-γ and cytotoxic T-cell induction, and plasmacytoid DCs produce IFN-α and lead to TH 2 responses that result in IL-4 production and enhanced antibody responses.

Fig1. Model of immune effector cell development. Hematopoietic stem cells differentiate into T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, macrophages, and B cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T-cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T-cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. Granulocytes (neutrophils, eosinophils, or basophils) are effector cells of the innate immune system and mediate anti-infectious agent activity by cytokine production, infectious agent killing, or both. TH 1 CD4+ T cells play an important role in defense against intracellular microbes and help in the generation of CD8+ cytotoxic T cells. TH 2 CD4+ T cells producing interferon (IFN) γ or interleukin (IL) 4, IL-5, or IL-13 regulate Ig class switching and determine the type of antibody produced. TH 17 cells secrete IL-17 and IL-22, TH 9 cells secrete IL-9, and TFH13 cells secrete IL-4, IL-5, and IL-13. TH 17 and TH 9 CD4 T cells are linked to mediation of autoimmune disease, and TFH13 cells are linked to IgE-mediated anaphylaxis. CD4+ T regulatory cells produce IL-10 and transforming growth factor (TGF)-β and downregulate T- and B-cell responses once the microbe has been eliminated. Each of the types of CD4+ T cells are regulated by different transcription factors, and the key transcription factors are shown in the circles above each CD4+ T-cell type.

As shown in Fig. 1, upon activation by DCs, T-cell subsets that produce IL-2, IL-3, IFN-γ, and/or IL-4, -5, -6, -10, and -13 are generated and exert positive and negative influences on effector T and B cells. For B cells, trophic effects are mediated by a variety of cytokines, particularly T cell–derived IL-3, -4, -5, and -6, that act at sequential stages of B-cell maturation, resulting in B-cell proliferation, differentiation, and ultimately antibody secretion. For cytotoxic T cells, trophic factors include inducer T-cell secretion of IL-2, IFN-γ, and IL-12.

Important types of immunomodulatory T cells that control immune responses are CD4 and CD8 Treg cells. These cells express the α chain of the IL-2 receptor (CD25), produce IL-10, and suppress both T- and B-cell responses. T regulatory cells (Tregs) are induced by immature DCs and play key roles in maintaining tolerance to self-antigens. Loss of Treg cells is the cause of organ-specific autoimmune disease in mice such as autoimmune thyroiditis, adrenalitis, and oophoritis and plays a role in inflammatory bowel disease (see “Immune Tolerance and Auto immunity” below, Chap. 361). Tregs also play key roles in controlling the magnitude and duration of immune responses to microbes. Normally, after the initial immune response to a microbe has eliminated the invader, Tregs are activated to suppress the antimicrobe response and prevent host injury. Some microbes have adapted to induce Treg activation at the site of infection to promote parasite infection and survival. In Leishmania infection, the parasite induces Treg accumulation at skin infection sites that dampens anti-Leishmania T-cell responses and prevents parasite elimination. Although B cells recognize native antigen via B-cell surface Ig receptors, B cells require T-cell help to produce high-affinity antibody of multiple isotypes that are the most effective in eliminating foreign antigen. In B-cell germinal centers, CD4 T cells that promote B-cell maturation and affinity maturation are termed T follicular helper (TFH) cells. T cell–B cell interactions that lead to high-affinity antibody production require (1) processing of native antigen by B cells and expression of peptide fragments on the B-cell surface for presentation to TH cells, (2) the ligation of B cells by both the TCR complex and the CD40 ligand, (3) induction of the process termed antibody isotype switching in antigen-specific B-cell clones, and (4) induction of the process of affinity maturation of antibody in the germinal centers of B-cell follicles of lymph node and spleen.

Naïve B cells express cell-surface IgD and IgM, and initial contact of naïve B cells with antigen is via binding of native antigen to B-cell surface IgM. T-cell cytokines, released following TH 2 cell contact with B cells or by a “bystander” effect, induce changes in Ig gene conformation that promote recombination of Ig genes. These events then result in the switching of expression of heavy chain exons in a triggered B cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody with the same V region antigen specificity as the original IgM antibody, for response to a wide variety of extracellular bacteria, protozoa, and helminths. CD40 ligand expression by activated T cells is critical for induction of B-cell antibody isotype switching and for B-cell responsiveness to cytokines. Patients with mutations in T-cell CD40 ligand have B cells that are unable to undergo isotype switching, resulting in lack of memory B-cell generation and the immunodeficiency syn drome of X-linked hyper-IgM syndrome.

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مواضيع ذات صلة

Immunotherapy

Immune Tolerance and Autoimmunity

Markers of Granulocytic Maturation

The Complement System Also Protects Against Infection

Monocytopoiesis

Eosinophil Production

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation

Neutrophil Granules and Their Content Proteins

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion