As T cells leave the thymus, they circulate in the bloodstream through secondary lymphoid tissues. Secondary lymphoid organs include the spleen, LNs, and mucosa-associated lymphoid tissues (MALT). Before interaction with their cognate antigen, these cells are designated naive T cells. Naive T cells leave the blood to enter LNs through specialized vessels called postcapillary venules and travel through the T cell–rich interfollicular zones. Naive T cells exit from these postcapillary venules, and upon antigenic recognition, remain in the node to proliferate and differentiate. If the naive T cells do not encounter cognate antigens, the cells exit LNs via lymphatic fluid back to the bloodstream and recirculate.

As naive T cells migrate through peripheral lymphoid organs, they sample various peptide–MHC complexes on APCs. These APCs include cells residing in the secondary lymphoid organs as well as those in tissues that sample their local environment and then migrate to the secondary lymphoid organs, hence concentrating antigen in these locations. If a naive T cell does not encounter its specific anti gen, it leaves the lymphoid tissue via the lymphatic system to reenter the bloodstream and repeat this process.

When a naive T cell recognizes its cognate antigen on an APC, a program of proliferation and differentiation transforms the naïve T cell into an effector T cell, now primed to respond rapidly upon encountering its corresponding antigen in the tissues. One important difference between naive and activated T cells is the cell surface expression of chemokine receptors and integrins. These receptors direct the cell to the appropriate tissue where the effector T cell is needed. Thus, as a part of the T-cell activation process, those receptors that direct the naive T cell in its pathway recirculating between the lymphatic organs and blood vessels are altered for those that direct the activated cell to the tissues, so that the effector T cell reaches the site of pathogen challenge.

CD4+ and CD8+ T cells undergo analogous differentiation pro cesses to acquire functional maturity but play distinct roles in the adaptive immune response to infection. Naive cells of both lineages are activated through peptide-MHC interaction with their TCRs, and their differentiation is influenced by a combination of signals, including TCR signal strength, co-stimulation by ligands that inter act with other T-cell surface receptors, and the local cytokine environment during antigen encounter. Integration of these signals promotes expression of signature transcription factors and key effector molecules, which allow the mature cell to perform its individualized function. Activated CD8+ T cells possess the machinery to induce death in host cells that express the appropriate peptide within the binding groove of MHC class I (see later), whereas CD4+ T cells exert their functions through the production of cytokines or by interacting with other immune cells through direct cell–cell contact following restimulation of their TCR by peptide presented by class II MHC. These so-called helper functions marshal and activate other cells of the immune system (Fig. 1). Until they encounter peptide–MHC, naive CD4+ T cells have the potential to develop into one of several effector sub sets, including Th1, Th2, Th17, and T follicular helper (Tfh) cells. Additional subsets have been defined recently, but these remain less well characterized and are not discussed here. Additionally, there is evidence that some CD4+ T cells have direct cytotoxic function, simi lar to their CD8+ counterparts (see below), but a full discussion of these cells is beyond the scope of this chapter.

Fig1. DIFFERENTIATION OF CD4+ T-HELPER SUBSETS. When activated, CD4+ T cells differentiate into distinct, functionally mature effector subsets. Various factors, including the cytokine milieu, promote the expression of signature transcription factors and effector molecules. CD4+ helper subsets are defined largely by their cytokine production driven by these key transcription factors. Th1 cells are induced by interferon γ (IFN-) and interleukin 12 (IL-12), express the transcription factor T-bet, and produce IFN-γ. IL-4 is the primary cytokine that promotes Th2 differentiation. Th2 cells are characterized by expression of GATA3 and production of IL-4, IL-5, and IL-13. Naive CD4+ cells that are activated in the presence of IL-6 and IL-21 differentiate into Th17 cells, typified by the expression of retinoic acid receptor–related orphan receptor γt (ROR-γt) and production of the IL-17 family of cytokines. T follicular helper (Tfh) cell differentiation is mediated by IL-21. These cells are characterized by the transcription factor B-cell lymphoma 6 protein (Bcl-6) and production of IL-21. If CD4+ helper differentiation and activity are not adequately controlled, imbalanced responses can lead to pathologic conditions.

Th1 Cells

Th1 cells activate macrophages, NK cells, and CD8+ T cells to com bat intracellular pathogens. Th1 cells also stimulate immunoglobulin class switching in B cells for the production of immunoglobulin G2a (IgG2a) antibodies that optimize clearance of viruses and extracellular bacteria (see Chapter 22). During priming of naive CD4+ T cells, several factors combine to promote differentiation along the Th1 pathway, including characteristics of the antigen, costimulatory signals from the presenting APC, and the cytokine microenvironment. Several cytokines are implicated in Th1 differentiation, but the two most critical are interferon γ (IFN-γ) and IL-12. IFN-γ produced by innate immune cells promotes Th1 differentiation by activating signal transducer and activator of transcription 1 (STAT1), a key signaling molecule that regulates T-bet, one of the signature transcription factors associated with Th1 cells. IL-12, produced by activated APCs and other innate immune cells, acts through a separate STAT4 dependent pathway to promote IFN-γ production. IL-12 also signals to upregulate its own receptor and the IL-18 receptor, thereby allowing IL-18 to act in concert with IL-12 to promote IFN-γ production, thus creating a “feedforward” cycle to amplify the Th1 response.

T-bet, a T-box family member, is the key transcription factor associated with Th1 differentiation and function. T-bet-deficient T cells are defective in their ability to differentiate into Th1 cells either in vitro or in vivo, and T-bet-deficient mice are unable to control Leishmania major infection, a well-characterized intracellular pathogen model that depends on the characteristic Th1 cytokines for clearance. Whereas T-bet is considered the “essential” factor that directs Th1 lineage determination, other transcription factors can play roles in optimal Th1 function.

Once differentiated, Th1 effector cells are characterized by pro duction of proinflammatory cytokines such as IFN-γ and tumor necrosis factor-α (TNF-α) that stimulate macrophages, NK cells, and CD8+ T cells to promote pathogen clearance. It is clear, however, that Th1 function must be balanced. Evidence from both ani mal models and human patients indicates that overexuberant Th1 responses drive inflammatory conditions and may lead to tissue destruction.

Th2 Cells

Th2 cells are critical for the immune response against extracellular parasites, such as helminths, through production of IL-4, IL-5, and IL-13. At initial sites of parasitic infection, epithelial cells of the target organs, including the skin, lungs, and intestines, and resident cells of the innate immune system sense parasite-derived products and pro duce Th2-inducing cytokines, including thymic stromal lymphopoietin (TSLP), IL-4, IL-25, and IL-33. These cytokines then act on innate immune cells, including basophils and DCs, as well as directly on naive CD4+ cells to promote Th2 differentiation.

IL-4 signaling is particularly critical to promote Th2 differentiation. Through interaction with its receptor, IL-4 activates STAT6. STAT6 plays a vital role in Th2 differentiation, as evidenced by the profound reduction in development of this lineage in Stat6 deficient mice. STAT6 activation leads to its nuclear translocation and subsequent induction of the transcription factor GATA binding factor 3 (GATA3), which, like T-bet for Th1 cells, is considered the master regulator of Th2 differentiation. GATA3 regulates Th2 cytokine production by binding and activating the “Th2 locus,” which includes the genes encoding IL-4, IL-5, and IL-13. When GATA3 function is abrogated, Th2 differentiation is virtually absent both in vitro and in vivo. Repression of Th1 differentiation occurs at least partially through GATA3-dependent inhibition of STAT4, thus interfering with Ifng gene transcription.

IL-4 produced by mature Th2 cells acts in a positive feedback loop to promote further Th2 cell differentiation in naive T cells as they encounter antigen. Th2-derived IL-4 also mediates IgE class switching in B cells. Soluble IgE binds to and crosslinks its high-affinity receptor FcεRI on basophils and mast cells, promoting production of histamine and serotonin as well as several cytokines, including IL-4, IL-13, and TNF-α. IL-5 produced from Th2 cells recruits eosinophils, whereas Th2-derived IL-13 promotes both the expulsion of helminths during parasitic infection and also the induction of airway hypersensitivity.

Th2 responses are critical for immunity against extracellular parasites, but excessive Th2 responses are associated with the pathologic conditions of allergy and airway hypersensitivity. The increase in asthma in the developed world has been linked to an imbalance of Th subsets with skewing toward “Th2-ness” in the population. Additional work is necessary to more firmly establish a molecular immunologic link to the epidemiology of these diseases. These studies will be enhanced by information gleaned from clinical trials of modulators of Th2 cytokines in asthma and other hypersensitivity disorders.

Th17 Cells

 The original description of Th1 and Th2 cells, indicating that not all mature CD4+ T cells were alike, led to the search for other CD4+ subsets. Extensive analyses of IL-17 and the cells that produce this cytokine demonstrate that Th17 cells are important for the control of extracellular bacterial and fungal infections. With excessive activity, however, these cells also appear to play an important role in autoimmune diseases through the production of proinflammatory cytokines, including IL-17A, IL-17F, IL-21, and IL-22.

Although IL-23 is a key regulator of Th17 cells, the IL-23 receptor is not expressed on naive CD4+ cells and hence could not explain the differentiation of cells into the Th17 subset. Subsequent studies demonstrated that the combination of transforming growth factor-β (TGF-β) with either IL-16 or IL-21 induces Th17 differentiation. The cytokines that are key mediators of Th17 differentiation and survival, including IL-6, IL-21, and IL-23, all activate STAT3. The critical role of this STAT family member was demonstrated in murine studies, when its deletion abrogated the ability of T cells to undergo Th17 differentiation. In humans, the importance of STAT3 was highlighted when it was identified as the genetic mutation present in many patients with hyper-IgE syndrome (HIES, or Job syn drome). HIES is a rare immunodeficiency syndrome characterized by recurrent staphylococcal skin abscesses, elevated serum IgE, and pneumatocele-forming pneumonias. Patients with HIES with STAT3 mutations have an impaired ability to form Th17 cells, which may explain part of their immunodeficiency. STAT3 regulates expression of many cytokine and cytokine receptor genes involved in Th17 generation or function, including IL-17A, IL-17F, IL-21, IL-21R, and IL-23R.

STAT3 is also important for induction of the signature Th17 transcription factor ROR-γt, which is a member of the retinoic acid related orphan receptor (ROR) family. In naive CD4+ cells, ROR-γt induces IL-17 gene transcription and promotes expression of the IL-23 receptor. ROR-γt deficiency only partially affects Th17 cells in vivo because of expression of the related transcription factor ROR-α, which is also expressed in T cells and is induced by IL-6/TGF-β in a STAT3 dependent manner. Cells deficient in both ROR-γt and ROR-α lose the ability to undergo Th17 differentiation, both in vitro and in vivo.

Th17 cells are induced during the response to extracellular bacteria and fungi, including Klebsiella pneumoniae, Bacteroides species, and Candida albicans. Indeed, some patients with chronic mucocutaneous candidiasis have been shown to have mutations in IL-17F and the IL-17 receptor genes. Excessive Th17 cell function also plays a role in autoimmune diseases, such as rheumatoid arthritis, psoriasis, and Crohn disease, and therapies targeting the Th17 axis have been approved or are under active clinical investigation for treating these disorders.

Tfh Cells

In addition to Th1, Th2, and Th17 subsets, naive CD4+ cells develop other functions dependent on the cytokines produced. Examples include recently described Th9, Th22, and Tfh cells. This latter sub set enhances the humoral immune response by providing help to B cells during germinal center reactions. Tfh cells express high levels of CXCR5, the receptor for the chemokine CXCL13. The expression of CXCR5 permits differentiating Tfh cells to migrate from the T-cell zone to the CXCL13-rich B-cell follicle in the LN, thereby allowing Tfh cells to interact with B cells and exert their function. In addition to CXCR5 expression, other signals, such as TCR signal strength and costimulatory molecules, are important for Tfh differentiation. A study using adoptive transfer of naive CD4+ cells expressing high- and low-affinity transgenic TCRs demonstrated that high-affinity TCR interactions preferentially developed into the Tfh subset. Tfh cells have higher expression of multiple costimulatory molecules, including CD40L, ICOS, and OX40, than other T helper subsets. Because costimulatory molecules enhance B-cell differentiation, the higher expression of these molecules on Tfh cells is hypothesized to positively correlate with the enhanced ability to facilitate B-cell antibody production. It appears that the expression of costimulatory molecules on Tfh cells is important not only for their function but also for their development and/or maintenance, because both mice and humans deficient in ICOS have fewer Tfh cells with reduced germinal center formation.

Similar to other CD4+ helper subsets, Tfh programming depends on a signature transcription factor, in this case B-cell lymphoma 6 protein (Bcl-6). In Tfh cells, Bcl-6 acts as a transcriptional repressor. Studies employing complementary methods of T cell–specific Bcl-6 deficiency and overexpression demonstrated that Bcl-6 expression in T cells is both necessary and sufficient for Tfh differentiation in vivo.

CD4+ Th Plasticity

 Although CD4+ T-helper differentiation was classically thought to be a model of lineage specification and differentiation, it is clear that there is more plasticity in the CD4+ Th subsets than was originally appreciated. Traditionally, Th subsets are associated with a signature cytokine(s) and transcription factor. However, recent data demonstrate CD4+ Th cells can express more than one cytokine, particularly in vivo, and even the transcriptional “master regulators” can be co expressed in the same cell. The mechanisms that underlie this plasticity and its functional relevance are areas of active investigation.

CD8+ Cytotoxic T Cells

The principal function of CD8+ cytotoxic T cells (CTLs) is to kill host cells that have been infected with pathogens or that have under gone deleterious changes, such as malignant transformation. Like CD4+ cells, naive CD8+ cells initially encounter peptide antigen and MHC on the surface of APCs in the secondary lymphoid organs. However, unlike CD4+ cells that are stimulated by class II MHC alleles on the APCs, CD8+ cells are engaged by class I MHC plus pep tide. For many years it remained unclear how APCs, which acquire peptide antigens largely by engulfing materials generated outside the cell, are able to present MHC class I–restricted peptides, which typically are generated within the cell. This conundrum was solved with the identification of “cross-presentation,” a mechanism by which APCs present engulfed antigens on both class I and class II alleles. Thus, tissue-resident phagocytic cells ingest virally-infected or malignantly transformed host cells, degrade the ingested material, and present the peptide antigens in the binding grooves of both class I and class II MHC alleles. These activated phagocytic cells then migrate to the LNs, where they encounter recirculating naive CD8+ cells. TCR engagement of foreign peptide–MHC class I complexes triggers activation of the CD8+ T cells and initiates CTL differentiation. As part of its activation program, the CTL changes its expression of integrins and chemokine receptors so that it can leave the circulation and enter the tissues, looking for host cells displaying the same antigen that induced CTL activation by the APC in the LN.

Once an appropriate target cell is identified in the tissues, the CTL is again stimulated through its TCR, this time by the peptide–MHC class I combination on the target cells. A structure similar to the IS forms between the CTL and the target cell. The CTL contains specialized granules that are transported to the contact site between the CTL and target. These granules are modified lysosomes that contain effector proteins, including perforin, granzymes, and granulysin. Perforin facilitates the entry of the granzymes into the cytosol of the target cell. The granzyme family, consisting of granzyme A, granzyme B, gran zyme H, granzyme K, and granzyme M, are proteases that degrade host cell proteins. Granzyme B is the best-studied family member and is known to cleave caspase 3, activating a proteolytic cascade leading to DNA degradation and apoptosis of the target cell (Fig. 2). Granzyme B also promotes cell death in a caspase-independent manner through cleavage of the proapoptotic protein Bid, promoting its migration to and disruption of the outer mitochondrial membrane, resulting in the release of cytochrome c. CTLs also produce cytokines, including IFN-γ, TNF-α, and IL-2. IFN-γ acts to inhibit viral replication in the affected tissues and also induces increased class I MHC expression, thus improving the ability of cells to stimulate the TCR on CTLs. IFN-γ synergizes with TNF-α for macrophage activation.

Fig2. CD8+ T-CELL CYTOLYTIC FUNCTION . Cytotoxic CD8+ T lymphocytes (CTLs) function primarily to kill host cells that have been infected by intracellular pathogens or that have undergone malignant transformation. After naive CD8+ cells encounter peptide–major histocompatibility complex (MHC) class I plus costimulation in secondary lymphoid organs, these activated CTLs leave the circulation and enter the tissues. There, upon interaction with a target expressing that same peptide–MHC class I, a CTL forms a lytic synapse, similar to the immunologic synapse, with the target. Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis. (From Abbas AK, Lichtman AH, Pillai S, Baker DL, Baker A. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2017.)

The transcription factors important for CD8+ T-cell effector differentiation include two members of the T-box family, T-bet and Eomesodermin (Eomes). Initially identified as the master Th1 determining transcription factor in CD4+ cells, T-bet also plays an essential role in CD8+ effector cell differentiation. Recent work has shown that T-bet expression is highest in short-lived effector cells and lower in CD8+ T cells destined to become memory cells (see later), suggesting that a gradient of T-bet expression controls the balance between different CD8+ effector fates. Eomes cooperates with T-bet in CTL function, and cells deficient in both factors are unable to generate CTLs in response to viral infection.

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الآخبار الصحية

طبيب يكشف أفضل مكمل غذائي لتحسين المزاج ودعم الصحة النفسية

دراسة جديدة تكشف أضرار الأطعمة الجاهزة على القلب ؟

6 أطعمة طبيعية تهدئ الزكام دون أدوية.. تعرف عليهم

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المزيد

مواضيع ذات صلة

The T-Cell Receptor Complex

Antigen Presentation: Creating the Ligand for the T-Cell Receptor

Therapeutic Passive Immunization and Monoclonal Antibody Therapy

Adverse Events Related to Intravenous Immunoglobulin Infusion

Therapeutic use of Immunoglobulin : Intravenous Immunoglobulin

Immunoglobulins

Complement and Cancer

Complement and T-Cell Immunity

Focusing Antigen on Follicular Dendritic Cells

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway