The major class of T cells is defined by its surface expression of the αβ TCR. This receptor has evolved primarily to recognize peptide antigens presented in a complex with class I or class II MHC proteins. αβ T cells differentiate into several different subsets, some of which (CD8+ T cells) act primarily to kill cells infected with intracellular microbes and others (CD4+ T cells) that act primarily to regulate the cellular and humoral immune responses. A small subset of αβ T cells that expresses the NK1.1 (CD161) NK cell antigen (NK-T cells) are usually CD4 and CD8 double negative, recognize glycolipid antigens presented by the CD1d molecule, and appear to be immunoregulatory based on their ability to release rapidly large quantities of the cytokines IFN-γ, IL-4, GM-CSF, TNF, and others.1 Details of the mechanisms by which T cells develop, acquiring their antigen specificity, and then are regulated as they encounter antigen in the peripheral tissues are discussed in chapter 3 of this Primer.4 An introductory overview is presented here.
Each individual T cell bears antigen receptors of a single specificity. A repertoire of T cells that can protect against the vast universe of microbial pathogens must therefore include a very large number of cells encoding a huge array of discrete TCRs. These receptors are somatically assembled from variable, diversity, and joining gene elements to generate mature VαJα chains and VβDβJβ chains (see chapter 3 of this Primer). The assembly of these gene elements is initiated by the lymphoid-specific recombinase-activating gene (RAG) 1 and RAG2 proteins, which cleave the DNA near the V, D, and J segments, and the gene segments are rejoined by a collection of non–lymphoid-specific DNA repair enzymes, including DNA-dependent protein kinase (DNA-PK), Ku, XRCC4, XLF, DNA ligase IV, and the Artemis nuclease.2 XRCC4, XLF, and DNA-PK help recruit the enzyme terminal deoxynucleotidyl transferase (TdT), which adds deoxynucleotides into some of the VDJ junctions, providing extra junctional diversity to the recombined gene sequences.3 The action of these recombinase enzymes results in the V, D, and J gene elements assembling in an apparently random process, producing a huge diversity of receptor sequences but also frequently producing nonfunctional genes. Selection of cells carrying functional TCR genes occurs in the thymus (Fig 6), a complex lymphoid organ located in the anterior mediastinum at the base of the neck.4 The thymus contains 3 compartments. The first, the subcapsular zone, is where bone marrow–derived prothymocytes begin to differentiate, proliferate, and rearrange their TCR β chains. The cells then move to the thymic cortex, where the α chain gene elements rearrange, potentially forming a functional, mature αβ TCR. In the cortex cells test whether their receptors have sufficient affinity for self-MHC molecules to permit them ultimately to recognize antigen-MHC complexes. This involves interactions between the developing lymphocyte and the specialized cortical epithelium.5 If the lymphocyte fails this positive selection, then it undergoes apoptosis and is cleared by thymic cortical macrophages. Finally, in the thymic medulla cells are screened for potential autoreactivity. This screening includes testing for reactivity for an extensive array of tissue-specific proteins that are expressed by a population of thymic medullary epithelial cells under the control of a gene called autoimmune regulator (AIRE). Defective expression of AIRE gives rise to the severe autoimmune syndrome called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy.6 Cells that recognize self-peptides expressed by these epithelial cells are removed by means of apoptosis, and cells that have survived this negative selection are exported to the circulation. Fewer than 5% of the developing T cells survive positive and negative selection.
Differentiation and maturation of T cells in the thymus. Hematopoietic stem cells, which do not express CD3, CD4, or CD8 but are committed to T-cell differentiation, move from the bone marrow to the thymic subcapsular zone. There they begin rearrangement of the TCR genes. Once a productive TCR β chain has been produced, they move to the thymic cortex, where TCR α chain rearrangement occurs and surface expression of the CD3, CD4, and CD8 proteins is induced. These CD4+CD8+ (double-positive) cells are positively selected on cortical epithelial cells for their ability to recognize self class I or class II HLA proteins. If the developing T cell has adequate affinity to recognize a self class I protein, then it retains expression of CD8 and extinguishes expression of CD4. If the cell recognizes a self class II protein, then it retains expression of CD4 and extinguishes expression of CD8. Selected CD4 or CD8 single-positive cells then move to the thymic medulla, where they are negatively selected on medullary epithelial cells to remove cells with excessive affinity for self-antigens presented in HLA molecules. Cells emerge from positive selection single positive for CD4 or CD8 expression and then are exported to the periphery. Cells that fail positive or negative selection are removed by apoptosis. A small fraction of cells differentiate to rearrange their TCR γ and δ chains, rather than their TCR α and β chains.
Modified with permission from Huston.
Approximately 90% to 95% of circulating T cells use the αβ TCR described above. The other 5% to 10% use an alternate heterodimeric TCR composed of γ and δ chains. The γ and δ chains also assemble by means of RAG1/RAG2-mediated rearrangement of V, D (for the δ chain only), and J elements. A portion of the γδ T cells is generated in the thymus, but a major fraction appears to be generated in an extrathymic compartment, resulting in cells that largely populate the gastrointestinal tract.7
T cell–antigen receptor complex
The antigen-specific α and β chains of the TCR associate with invariant accessory chains that serve to transduce signals when the TCR binds to antigen-MHC complexes.8 These accessory chains make up the CD3 complex, consisting of the transmembrane CD3γ, CD3δ, and CD3ε chains plus a largely intracytoplasmic homodimer of 2 CD3ζ chains. Although the stoichiometry of the CD3 complex is not definitively established, it appears that each TCR αβ pair associates with a CD3γε heterodimer, a CD3δε heterodimer, and a CD3ζ homodimer (Fig 7).
The TCR complex and T-cell activation. A, the complete TCR complex includes the rearranged TCR α and β chains and also the CD3γ, CD3δ, CD3ε, and CD3ζ chains. The CD3 chains contain ITAMs in their cytoplasmic domains that can be phosphorylated to activate the intracellular signaling cascade for T-cell activation. The signaling protein tyrosine kinases Lck and Fyn associate with the intracellular portions of the CD4 and CD3 chains, respectively. TCR engagement by MHC plus peptide without the presence of costimulatory proteins fails to activate phosphorylation of the CD3 ITAMs and results in anergy. B, TCR engagement by MHC plus peptide with costimulatory interactions between CD28 on the T cell and CD80 or CD86 (B7.1 or B7.2) on the APC results in Lck- and Fyn-dependent phosphorylation of the CD3 chains and recruitment of the adapter protein zeta-chain-associated protein kinase 70 (ZAP-70), to the CD3 complex. This leads to phosphorylation of ZAP-70, which induces the downstream program of T-cell activation. C, polyclonal activation of T cells can be elicited by superantigens, which interact outside the peptide-binding groove with the β1 chain of the class II molecule and with all Vβ chains of a particular subclass. This activates CD4-independent but Fyn-dependent phosphorylation of the CD3 chains, recruitment and phosphorylation of ZAP-70, and cell activation.
Interaction of the TCR/CD3 complex with antigenic peptide presented in an HLA molecule provides only a partial signal for cell activation. Full activation requires the additional participation of a costimulatory molecule, such as CD28 on the T cell and CD80 (also designated B7.1) or CD86 (B7.2) on the APC (Fig 7).9 In fact, interaction of peptide-MHC with the TCR without a costimulator can lead to an anergic state of prolonged T-cell nonresponsiveness.
The cytoplasmic portions of each of the CD3 chains contain sequence motifs designated immunoreceptor tyrosine-based activation motifs (ITAM). When key tyrosines in these ITAMs are phosphorylated by the receptor-associated kinases Lck and Fyn, this initiates an activation cascade involving the proteins zeta-chain-associated protein kinase 70 (ZAP-70), and, farther downstream, Linker of Activated T cells (LAT) and SH2 domain containing leukocyte protein of 76kDa (SLP-76). Activation of these proteins leads to stimulation of phospholipase C, activation of the G proteins Ras and Rac, and both protein kinase C and the mitogen-associated protein kinases. Together, this complex of activation events leads to activation of genes that control lymphocyte proliferation and differentiation.
The pathways that downregulate this activation pathway are becoming increasingly well defined. The membrane molecule CD45 is a key tyrosine phosphatase that occupies a central position in this deactivating process. In addition, a specific receptor-ligand pair, programmed death 1 and programmed death ligand 1, transduces signals to the activated lymphocyte to inhibit its proliferation and effector functions, thus extinguishing the T-cell response.10 Mutations affecting the function of many of the molecules involved in intracellular lymphoid cell-signal transduction processes underlie congenital primary immunodeficiency syndromes (see chapter 15 of this Primer).11
During their progress through the thymus, αβ T cells differentiate into discrete subpopulations, each with defined repertoires of effector functions. The major subsets are defined by their selective surface expression of CD4 or CD8. In the thymus most developing T cells follow a developmental program in which in the cortex they first express neither CD4 nor CD8 (double negative) and then express both CD4 and CD8 (double positive).12 Double-positive cells are tested by means of positive selection in the thymic cortex, and those that are selected on class I MHC molecules become CD4−CD8+ and those that are selected on class II MHC molecules become CD4+CD8−. The fact that the CD4 molecule contributes to a stable interaction of the developing T cell with class II MHC molecules on the selecting APC and that CD8 contributes to interactions with class I molecules is central to the association of CD4 with class II MHC–restricted antigen recognition and of CD8 with class I–restricted antigen recognition. Cells that survive positive selection then move to the thymic medulla for negative selection and export to the periphery. In the blood and secondary lymphoid organs, 60% to 70% of T cells are CD4+CD8− (CD4+) and 30% to 40% are CD4−CD8+ (CD8+). CD4+ T cells are generally designated helper cells and activate both humoral immune responses (B-cell help) and cellular responses (delayed-type hypersensitivity responses and others). CD8+ cells show a major cytotoxic activity against cells infected with intracellular microbes and against tumor cells but also contain regulatory cells that downregulate immune responses (suppressor cells). A portion of the circulating CD4+ T cells play an important regulatory role that acts to down modulate immune responses. These regulatory T (Treg) cells fall into 2 groups. The first group develops its regulatory function in the thymus and is known as natural Treg cells. These cells are characterized by surface expression of the CD4 and CD25 antigens and by nuclear expression of the forkhead box protein 3 (Foxp3) transcription factor that is essential for their development. A major portion of this population’s regulatory activity is due to its secretion of the immunomodulatory cytokines TGF-β and IL-10.13 Under some conditions, suppression of effector T-cell proliferation by Treg cells requires cell-cell contact. In this situation it has been reported that TGF-β acts in a membrane-associated form.14 The second group of Treg cells is thought to differentiate in the periphery from naive CD4+ T cells. Because they appear to develop in response to stimulation with specific antigen, they are called adaptive or induced Treg cells. Their differentiation appears to depend on the presence of IL-10 during their initial activation. Expression of Foxp3 is variable in this subset, and IL-10 is a prominent secreted product, with TGF-β also participating.15 The phenotype of these cells can be unstable, with Foxp3 expression disappearing soon after withdrawal of the inductive IL-10 or TGF-β. Recent studies have indicated that epigenetic modification of the Foxp3 locus, in the form of both histone acetylation and altered DNA methylation in the area around the Foxp3 promoter, are essential for establishment of stable expression of Foxp3 and maintenance of the Treg cell phenotype.16
Approximately 5% to 10% of T cells in the peripheral blood, lymph nodes, and spleen are CD4−CD8−. Some of these cells use αβ TCRs, and others use γδ TCRs. Double-negative cells do not recognize antigen in the context of MHC class I or II. Some of these cells recognize antigen in the class I–related protein CD1 that is adapted to presentation of glycolipid components of mycobacteria and other microbes. A subset of double-negative γδ T cells recognizes the MHC class I chain–related proteins designated MIC.
Both CD4+ and CD8+ T cells differentiate into functionally distinct subsets after exposure to antigen. This is best described for the transition of CD4+ T cells from naive to effector populations. Resting naive CD4+ T cells (designated TH cells) release very low levels of cytokines. Early after stimulation by antigen and APCs, the TH cells begin to produce IL-2 and are designated TH0. As the TH cells continue to respond to the activating signal, they progress toward polar extremes of differentiation designated TH1, TH2, and TH17 depending on the nature of the cytokines present at the site of activation.17 IL-12 produced by macrophages or NK cells induces differentiation toward TH1; IL-4 produced by NK1.1+ T cells, basophils, or mast cells induces differentiation toward TH2; and TGF-β and IL-6 produced by yet to be defined cells induce differentiation toward TH17. TH1 cells are characterized by their expression of the T-box transcription factor (T-bet) and by the production of IL-2, IFN-γ, and lymphotoxin. TH2 cells are characterized by their expression of the transcription factor GATA3 and produce IL-4, IL-5, IL-9, IL-13, and GM-CSF, and TH17 cells express the transcription factor Retinoic-acid-related Orphan Receptor C isoform 2 (RORC2) and produce the cytokines IL-6 and IL-17 (see chapter 3 of this Primer), 18 TH17 cells are induced early in the adaptive response to extracellular bacteria and help to recruit the neutrophil response that eliminates these pathogens. They also direct the destructive inflammatory responses that are part of many autoimmune diseases. TH1 and TH2 cells often participate together in immune responses; however, after prolonged immunization, the response can become dominantly TH1 or TH2 like. Generally, TH1 cells support cell-mediated immune responses, and TH2 cells support humoral and allergic responses. CD8+ T cells also can manifest type 1 and type 2 cytokine responses, in which case the cells are designated cytotoxic T cell type 1 and cytotoxic T cell type 2.19 Understanding the factors that govern whether a TH response adopts a predominantly TH1-type, TH2-type, or TH17-type response is crucial to the allergist/clinical immunologist. Recent progress using immunization with different types of adjuvants (eg, CpG DNA) demonstrates the feasibility of reprogramming, in atopic patients, allergic TH2-type responses to nonallergic TH1-type responses.
Conventional antigens bind to a subset of MHC molecules and to a very small fraction of the huge array of TCRs. Thus a conventional peptide antigen activates only a very small fraction of the total pool of T cells. Superantigens, in contrast, are microbial products that bind to large subsets of TCR proteins and MHC molecules, so that a single superantigen can activate up to 20% or more of the total T cells in the body. The superantigen does this by binding without proteolytic processing to the MHC molecule outside of the antigen-binding groove and to TCR proteins outside of their antigen-MHC binding site (Fig 7). For example, the toxic shock syndrome toxin 1 produced by Staphylococcus aureus can activate all T cells with TCRs that use the Vβ2 and Vβ5.1 chains. The activation of large numbers of T cells induced by superantigens results in the massive release of cytokines producing clinical conditions, such as toxic shock syndrome.21
- Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name?. Nat Rev Immunol. 2004;4:231–237
- Gellert M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem. 2002;71:101–132
- Nguyen HH, Zemlin M, Ivanov II, Andrasi J, Zemlin C, Vu HL, et al. Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire. J Virol. 2007;81:9331–9338
- Miller JF. The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev. 2002;185:7–14
- Nitta T, Murata S, Ueno T, Tanaka K, Takahama Y. Thymic microenvironments for T-cell repertoire formation. Adv Immunol. 2008;99:59–94
- Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009;27:287–312
- Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev. 2009;228:9–22
- Nurieva RI, Liu X, Dong C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev. 2009;229:88–100
- Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229:114–125
- Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125:S182–S194
- von Boehmer H, Kisielow P, Kishi H, Scott B, Borgulya P, Teh HS. The expression of CD4 and CD8 accessory molecules on mature T cells is not random but correlates with the specificity of the alpha beta receptor for antigen. Immunol Rev. 1989;109:143–151
- Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27
- Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med. 2001;194:629–644
- Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009;30:626–635
- Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?. Nat Rev Immunol. 2009;9:83–89
- Sallusto F, Lanzavecchia A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur J Immunol. 2009;39:2076–2082
- Unutmaz D. RORC2: the master of human Th17 cell programming. Eur J Immunol. 2009;39:1452–1455
- Thomas MJ, MacAry PA, Noble A, Askenase PW, Kemeny DM. T cytotoxic 1 and T cytotoxic 2 CD8 T cells both inhibit IgE responses. Int Arch Allergy Immunol. 2001;124:187–189
- Racila DM, Kline JN. Perspectives in asthma: molecular use of microbial products in asthma prevention and treatment. J Allergy Clin Immunol. 2005;116:1202–1205
- Larkin EA, Carman RJ, Krakauer T, Stiles BG. Staphylococcus aureus: the toxic presence of a pathogen extraordinaire. Curr Med Chem. 2009;16:4003–4019
David D. Chaplin The Journal of Allergy and Clinical Immunology
Volume 125, Issue 2, Supplement 2 , Pages S3-S23, February 2010 Overview of the immune response