T lymphocytes play multiple roles in defending against microbes, with a major role in cell-mediated immunity against intracellular pathogens.
Cell-mediated immunity is crucial for eliminating microbes residing and replicating inside host cells, common in viral, bacterial, fungal, and protozoan infections.
This process involves T lymphocytes interacting with other cells like phagocytes, infected host cells, or B lymphocytes. It also requires interaction of naive T cells with dendritic cells, which present antigens in secondary lymphoid organs.
Defense Mechanisms
Phagocytes: Ingest microbes, killing them within phagocytic vesicles but some microbes resist this.
CD4+ helper T cells: Enhance macrophage ability to kill ingested microbes.
Neutrophils and Eosinophils: Destroy extracellular microbes and helminthic parasites, respectively, with CD4+ T cells producing activating cytokines.
CD8+ cytotoxic T lymphocytes (CTLs): Kill infected cells, eliminating infection reservoirs, especially for viruses replicating in the cytosol and nucleus.
T cell–mediated immunity
A: Microbes ingested by phagocytes can survive within vesicles or escape to the cytosol, evading microbicidal mechanisms. Helper T cells enhance phagocyte killing functions via cytokines and CD40-ligand (CD40L).
B: Viruses infect and replicate in various cells, including nonphagocytic cells. CTLs combat these microbes by killing infected cells. CTLs also target cells where ingested microbes have escaped into the cytosol.
Roles of T Cells
CD4+ T cells help B cells produce antibodies (humoral immune responses).
CD8+ CTLs can kill cancer cells, as discussed in Chapter 10.
T cell responses require naive T cells to recognize antigens displayed by dendritic cells in secondary lymphoid organs.
Activation and Function of T Lymphocytes
T lymphocytes' functions include activating phagocytes, killing infected and tumor cells, and aiding B cells.
These processes require T lymphocytes to interact with phagocytes, infected host cells, or B lymphocytes.
Initiation of T cell responses requires naive T cells to recognize antigens displayed by dendritic cells in secondary lymphoid organs.
T cell specificity for peptides displayed by MHC molecules ensures response only to antigens inside host cells.
Questions Addressed
What stimuli are needed to activate naive T lymphocytes and initiate cell-mediated immune responses?
How are the few naive T cells specific for any microbe converted into the large number of effector T cells that have specialized functions and the ability to eliminate diverse microbes?
What biochemical signals are required for the activation of T lymphocytes?
Steps in T Cell Responses
Naive T lymphocytes recognize antigens in secondary lymphoid organs and respond by proliferation and differentiation into effector cells.
These effector cells perform their functions upon activation by the same antigens in infected tissues.
Naive T cells express antigen receptors and coreceptors but can't perform effector functions.
Differentiated effector cells can perform these functions at any infection site.
This chapter focuses on initial responses of naive T cells to antigens in secondary lymphoid organs.
Sequential Steps in T Cell Activation
Naive T lymphocytes respond to host cell-associated microbial antigens through sequential steps, increasing antigen-specific T cells and differentiating naive T cells into effector and memory cells.
Cytokine Secretion and Receptor Expression: Early responses include cytokine secretion for proliferation and differentiation, and increased expression of cytokine receptors.
Clonal Expansion: Interleukin-2 (IL-2), produced by antigen-activated T cells, stimulates cell proliferation, rapidly increasing antigen-specific lymphocytes.
Differentiation: Activated lymphocytes differentiate into effector T cells that eliminate microbes.
Migration to Infection Sites: Many effector T cells leave lymphoid organs, enter circulation, and migrate to infection sites to eradicate microbes. Some activated T cells stay in secondary lymphoid organs to signal B cells for antibody responses.
Memory Cell Development: Some T cell progeny develop into memory T cells, which are long-lived, circulate in blood or reside in tissues, and respond rapidly to subsequent exposure to the same microbe.
Decline of Immune Response: As effector T cells eliminate the infectious agent, the stimuli that triggered T cell expansion and differentiation are also eliminated. Most cells in expanded clones die, returning the system to a resting state, with only memory cells remaining.
Differences between CD4+ and CD8+ T lymphocytes
CD4+ and CD8+ T lymphocytes follow the same sequence of events, but differ in properties and effector functions.
Naive and effector T cells have different circulation and migration patterns, which are critical for their different roles in immune responses.
Naive T lymphocytes constantly recirculate through secondary lymphoid organs, searching for foreign protein antigens.
Antigen Presentation and T Cell Activation
Microbial antigens are transported from entry points to lymphoid organs where recirculating naive T cells are located.
Dendritic cells are the most efficient antigen-presenting cells (APCs) for transporting antigens to lymph nodes and stimulating naive T cells.
In secondary lymphoid organs, dendritic cells process antigens and display peptides bound to MHC molecules.
When a T cell recognizes an antigen, it is transiently arrested on the dendritic cell and receives activating signals, leading to proliferation and differentiation.
Cells then leave the lymphoid organ and migrate preferentially to the inflamed tissue, the original source of the antigen.
T Cell Activation and Regulation
The chapter describes the stimuli required for T cell activation and regulation, biochemical signals generated by antigen recognition, biologic responses of lymphocytes, and regulation of T cell responses.
Induction Phase: Naive CD4+ and CD8+ T cells recognize peptides derived from protein antigens, presented by DCs in peripheral lymphoid organs. The T lymphocytes are stimulated to proliferate and differentiate into effector cells, many of which enter the circulation.
Migration of Effector T cells: Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues.
T cell Effector functions: CD4+ T cells recruit and activate phagocytes to destroy microbes, and CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells.
Steps in T Lymphocyte Activation
Naive T cells recognize MHC-associated peptide antigens displayed on antigen-presenting cells (APCs) and other signals.
T cells produce interleukin-2 (IL-2) and express receptors for IL-2, leading to an autocrine pathway of cell proliferation.
This results in expansion of the clone of T cells that are specific for the antigen.
Some of the progeny differentiate into effector cells, which serve various functions in cell-mediated immunity, and some differentiate into memory cells, which survive for long periods.
Antigen Recognition and Costimulation
Initiation of T cell responses requires multiple receptors on T cells recognizing their specific ligands on APCs.
The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
CD4 or CD8 coreceptors on the T cells bind to MHC molecules on the APC and help the TCR complex deliver activating signals.
Adhesion molecules strengthen the binding of T cells to APCs.
Costimulators, expressed on APCs after encounter with microbes, bind to their receptors on the naive T cells, and promote responses, especially to infectious pathogens.
Cytokines secreted by various cell types bind to receptors on the T cells and amplify the T cell response and direct it along various differentiation pathways.
Recognition of Peptide-MHC Complexes
The TCR and the CD4 or CD8 coreceptor together recognize complexes of peptide antigens and MHC molecules on APCs, providing the initiating signal for T cell activation.
TCRs on CD4+ and CD8+ T cells consist of α and β chains that participate in antigen recognition.
The TCR of a T cell specific for a foreign peptide recognizes the displayed peptide and residues of the MHC molecule around the peptide-binding cleft.
Mature MHC-restricted T cells express either CD4 or CD8, which bind to the same MHC molecules as the TCR and are required for signaling.
CD4 or CD8 binds the class II or class I MHC molecule, respectively, bringing signaling enzymes close to the CD3 and ζ tails to initiate signal transduction.
Protein antigens ingested by APCs from the extracellular milieu are processed into peptides displayed by class II MHC molecules.
Protein antigens present in the cytosol are processed by proteasomes into peptides displayed by class I MHC molecules.
Coreceptor Specificity in T Cell Activation
Because of the specificity of coreceptors for different classes of MHC molecules, CD4+ and CD8+ T cells recognize peptides generated through different protein processing pathways.
The TCR and its coreceptor need to be engaged simultaneously to initiate the T cell response, and multiple TCRs likely need to be triggered for T cell activation to occur.
Once these conditions are achieved, the T cell begins its activation program.
Receptors and Ligands in T Cell Activation and Inhibition
A: Major surface molecules of CD4+ T cells involved in activation and their corresponding ligands on antigen-presenting cells (APCs). CD8+ T cells use similar molecules, except TCR recognizes peptide-class I MHC complexes, and the coreceptor is CD8, recognizing class I MHC.
CD3: Composed of three polypeptide chains, δ, ε, and γ, arranged in two pairs (δε and γε).
Immunoreceptor tyrosine-based activation motifs (ITAMs) are regions of cytosolic tails of signaling proteins phosphorylated on tyrosine residues, becoming docking sites for other tyrosine kinases.
Immunoreceptor tyrosine-based inhibitory motifs are regions of signaling proteins that are sites for tyrosine phosphatases that counteract actions of ITAMs.
Important properties of major surface molecules of T cells involved in functional responses. Cytokines and cytokine receptors are not listed here.
LFA-1 is an integrin involved in leukocyte binding to endothelium and T cell binding to APCs.
Antigen Recognition and Signal Transduction
Different T cell molecules recognize antigens and deliver biochemical signals to the cell as a result of antigen recognition.
CD3 and ζ proteins are noncovalently attached to the T cell receptor (TCR) α and β chains by interactions between charged amino acids in the transmembrane domains of these proteins.
The figure illustrates a CD4+ T cell; the same interactions are involved in the activation of CD8+ T cells, except that the coreceptor is CD8 and the TCR recognizes a peptide–class I MHC complex.
The biochemical signals that lead to T cell activation are triggered by a set of proteins linked to the TCR that are part of the TCR complex and by the CD4 or CD8 coreceptor.
In lymphocytes, antigen recognition and subsequent signaling are performed by different sets of molecules.
The TCR αβ heterodimer recognizes antigens but cannot transmit biochemical signals.
TCR Complex and Signal Transduction
The TCR is noncovalently associated with a complex of transmembrane signaling proteins, including three CD3 proteins and a ζ chain, forming the TCR complex.
While TCR chains vary among T cell clones to recognize diverse antigens, the signaling functions of the TCR complex are the same in all clones, and the CD3 and ζ proteins are invariant.
T cells can be activated by molecules that bind to TCRs of many or all clones, regardless of peptide-MHC specificity.
Some microbial toxins bind to TCRs and MHC class II molecules on APCs outside the peptide-binding cleft, activating many T cells and causing excessive cytokine release and systemic inflammatory disease.
These toxins are called superantigens because they engage more TCRs than typical antigens.
Role of Adhesion Molecules in T Cell Responses
Adhesion molecules on T cells recognize their ligands on APCs and stabilize the binding of T cells to the APCs.
Most TCRs bind peptide-MHC complexes with low affinity.
Adhesion of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
Integrins are the major adhesion molecules, with leukocyte function–associated antigen 1 (LFA-1) being the primary T cell integrin involved in binding to APCs.
The ligand for LFA-1 on APCs is intercellular adhesion molecule 1 (ICAM-1).
Integrins and T Cell Binding
On resting naive T cells, the LFA-1 integrin is in a low-affinity state.
Antigen recognition by a T cell increases the affinity of that cell’s LFA-1, strengthening binding to the APC.
Integrin-mediated adhesion is critical for the ability of T cells to bind to APCs displaying microbial antigens.
Integrins also play an important role in directing the migration of effector T cells and other leukocytes from the circulation to sites of infection.
Role of Costimulation in T Cell Activation
Full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen.
Costimulators provide stimuli to T cells that function with stimulation by antigen; these are often called second signals for T cell activation.
The best-defined costimulators are B7-1 (CD80) and B7-2 (CD86), expressed on APCs and increased upon encountering microbes.
These B7 proteins are recognized by CD28, expressed on most T cells.
CD28-mediated Signaling
The binding of B7 on APCs to CD28 on T cells generates signals that work with signals from TCR recognition of antigen presented by MHC proteins.
CD28-mediated signaling is essential for naive T cell responses; without CD28:B7 interactions, antigen recognition is insufficient.
Costimulation ensures that naive T lymphocytes are maximally activated by microbial antigens and not by harmless substances or self-antigens.
Microbes stimulate the expression of B7 costimulators on APCs.
Most infections do not trigger harmful reactions against self-antigens due to numerous control mechanisms preventing autoimmunity.
Additional Molecules in T Cell Responses
Inducible costimulator (ICOS), homologous to CD28, is important in the development and function of follicular helper T cells during germinal center B cell responses.
The CD28 family includes inhibitory receptors CTLA-4 and PD-1, which regulate immune responses.
CD40 ligand (CD40L, or CD154) on activated T cells and CD40 on APCs enhance T cell activation indirectly.
CD40L on a T cell binds to CD40 on APCs, activating the APCs to express more B7 costimulators and secrete cytokines (e.g., IL-12).
CD40L–CD40 interaction promotes T cell activation by making APCs better at stimulating T cells.
Resting APCs and Costimulation
Resting antigen-presenting cells (APCs), which have not been exposed to microbes or adjuvants, may present peptide antigens but do not express costimulators and are unable to activate naive T cells.
T cells that recognize antigen without costimulation may die or become unresponsive (tolerant) to subsequent exposure to antigen.
Microbes, as well as cytokines produced during innate immune responses to microbes, induce the expression of costimulators, such as B7 molecules, on the APCs.
The B7 costimulators are recognized by the CD28 receptor on naive T cells, providing signal 2. In conjunction with antigen recognition (signal 1), this recognition initiates T cell responses.
Activated APCs also produce cytokines that stimulate the differentiation of naive T cells into effector cells.
Adjuvants and Vaccines
The role of costimulation in T cell activation explains why protein antigens used in vaccines fail to elicit T cell-dependent immune responses unless administered with substances that activate APCs, especially dendritic cells.
These substances are called adjuvants, and they induce the expression of costimulators on APCs and stimulate the APCs to secrete cytokines that activate T cells.
Most adjuvants are products of microbes or mimic microbes, binding to pattern recognition receptors of the innate immune system.
Numerous adjuvants have been developed for human vaccines, working, at least in part, by eliciting innate immune responses that activate APCs to increase expression of costimulators and secretion of T cell–activating cytokines.
In mRNA vaccines, lipids that encapsulate the RNA function as adjuvants.
Adjuvants trick the immune system into responding to purified protein antigens in a vaccine as if these proteins were parts of infectious microbes.
Stimuli for Activation of CD8+ T Cells
Activation of naive CD8+ T cells is stimulated by recognition of class I MHC–associated peptides and requires costimulation and helper T cells.
CD8+ T cell responses differ from CD4+ T lymphocyte responses.
Key Differences:
The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cell) to be cross-presented by dendritic cells
The differentiation of naive CD8+ T cells into fully active CTLs and memory cells may require the concomitant activation of CD4+ helper T cells.
CD4+ Helper T Cells Role
When virus-infected or tumor cells are ingested by dendritic cells, the APCs may present viral or tumor antigens from the cytosol in complex with class I MHC molecules and from vesicles in complex with class II MHC molecules.
Thus, both CD8+ T cells and CD4+ T cells specific for viral or tumor antigens are activated near one another.
The CD4+ T cells may produce cytokines or membrane molecules that help to activate the CD8+ T cells.
CD4+ helper cells also enhance the expression of costimulatory molecules on APCs that activate CD8+ T cells.
The requirement for helper T cells in CD8+ T cell responses is the likely explanation for the increased susceptibility to viral infections and cancers in patients infected with HIV, which kills CD4+ but not CD8+ T cells.
Biochemical Pathways of T Cell Activation
Following the recognition of antigens and costimulators, T cells express proteins involved in proliferation, differentiation, and effector functions.
Naive T cells have low protein synthesis levels until antigen recognition triggers new gene transcription and protein synthesis.
These newly expressed proteins mediate many subsequent responses of the T cells, induced by signal transduction pathways from the TCR complex and costimulatory receptors.
Antigen Recognition and Signaling
Antigen recognition activates several biochemical signaling events, including enzyme activation (kinases), adaptor protein recruitment, and transcription factor production.
These pathways are initiated when TCR complexes and the appropriate coreceptor bind to MHC-peptide complexes on APCs.
Proteins in both APC and T cell membranes move to the region of cell-to-cell contact, with the TCR complex, CD4/CD8 coreceptors, and CD28 coalescing to the center and integrins moving to form a peripheral ring.
This redistribution, forming the immune synapse, is crucial for optimal induction of activating signals in the T cell, and may also target effector molecules and involve termination of lymphocyte activation.
T Cell Activation Mechanism
Antigen recognition engages the TCR and CD4 or CD8 coreceptor simultaneously.
The cytoplasmic tails of CD4 and CD8 have an attached protein tyrosine kinase called LCK, which is constitutively active and initiates the signaling cascade.
Transmembrane signaling proteins, including CD3 and ζ chains, are associated with the TCR and contain immunoreceptor tyrosine-based activation motifs (ITAMs), critical for signaling.
LCK, brought near the TCR complex by CD4 or CD8, phosphorylates tyrosine residues within the ITAMs of the CD3 and ζ proteins, launching signal transduction.
Phosphorylated ITAMs of the ζ chain become docking sites for ZAP-70, which is also phosphorylated by LCK and activated.
Active ZAP-70 then phosphorylates adaptor proteins and enzymes, which assemble near the TCR complex and mediate additional signaling events.
Proteins Produced by Antigen-Stimulated T Cells
Antigen recognition by T cells results in the synthesis and expression of various proteins.
The kinetics of production of these proteins are approximations and may vary in different T cells and with different types of stimuli.
The functions of some of the surface proteins expressed on activated T cells, such as CD69, IL-2 receptor, CD40 ligand, and CTLA-4.
Signal Transduction Pathways in T Lymphocytes
Antigen recognition by T cells induces early signaling events, including tyrosine phosphorylation of molecules of the T cell receptor (TCR) complex and the recruitment of adaptor proteins to the site of T cell antigen recognition.
These early events lead to the activation of several biochemical intermediates, which in turn activate transcription factors that stimulate transcription of genes whose products mediate the responses of the T cells.
The signaling pathways linked to TCR complex activation lead to the production of functional transcription factors.
Activation Pathway of NFAT
NFAT (Nuclear factor of activated T cells): A transcription factor present in an inactive phosphorylated form in the cytosol of resting T cells.
NFAT activation and nuclear translocation depend on the concentration of calcium ( Ca2+ ) ions in the cytosol.
Pathway is initiated by phosphorylation and activation of phospholipase Cγ (PLCγ) by a kinase, ITK, attached to one of the adaptor proteins.
IP3 binds to IP3 receptors on the endoplasmic reticulum (ER) membrane and mitochondria, releasing Ca2+ into the cytosol.
In response to calcium loss from the ER, a plasma membrane calcium channel opens, leading to influx of extracellular Ca2+, causing a sustained increase in cytosolic Ca2+ concentration.
Elevated cytosolic Ca2+ leads to activation of calcineurin, a phosphatase that removes phosphates from cytoplasmic NFAT, enabling it to migrate into the nucleus.
In the nucleus, NFAT binds to and activates the promoters of several genes, including those encoding the T cell growth factor IL-2 and components of the IL-2 receptor.
Inhibition of Calcineurin
Calcineurin inhibitors (cyclosporine and tacrolimus) block the phosphatase activity of calcineurin, suppressing NFAT-dependent cytokine production by T cells.
These drugs are widely used as immunosuppressants to prevent graft rejection
RAS/ RAC–MAP Kinase Pathways
Involve guanosine triphosphate (GTP)–binding RAS and RAC proteins, adaptor proteins, and a cascade of enzymes that activate mitogen-activated protein (MAP) kinases.
Initiated by ZAP-70–dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane, leading to RAS or RAC recruitment and activation by exchange of bound guanosine diphosphate (GDP) with GTP.
Active forms of RAS and RAC (RAS•GTP and RAC•GTP) initiate distinct enzyme cascades, activating different MAP kinases.
Terminal MAP kinases, such as extracellular signal–regulated kinase (ERK) and c-JUN amino-terminal kinase (JNK), induce expression of c-FOS and phosphorylation of c-JUN.
c-FOS and phosphorylated c-JUN combine to form the transcription factor activator protein 1 (AP-1), which enhances the transcription of several T cell genes.
Role of Protein Kinase C (PKCθ) and NF-κB Pathway
TCR signaling involves activation of the θ isoform of serine-threonine kinase protein kinase C (PKCθ), leading to activation of the transcription factor NF-κB.
PKC is activated by diacylglycerol, generated by PLC-mediated hydrolysis of PIP2 in the membrane.
PKCθ acts through adaptor proteins to activate NF-κB.
PI-3 Kinase and AKT Activation
TCR signal transduction involves a lipid kinase called PI-3 kinase, which phosphorylates the membrane phospholipid PIP2 to generate phosphatidyl inositol (3,4,5)-trisphosphate (PIP3).
PIP3 is required for the activation of several targets, including a serine-threonine kinase called AKT.
AKT has multiple roles, including stimulating expression of antiapoptotic proteins, promoting survival of antigen-stimulated T cells, and stimulating protein translation, promoting cell survival and growth.
Rapamycin (sirolimus) is a drug that binds to and inactivates mTOR, and is used to treat graft rejection.
Transcription Factors and Effector Molecules
Various transcription factors induced or activated in T cells, including NFAT, AP-1, and NF-κB, stimulate transcription and production of cytokines, cytokine receptors, cell cycle inducers, and effector molecules, such as CD40L.
All signals are initiated by antigen recognition, as binding of the TCR and coreceptors to peptide-MHC complexes brings together critical enzymes and substrates in T cells.
Recognition of costimulators, such as B7 molecules, by their receptor CD28 is essential for full T cell responses.
Biochemical signals transduced by CD28 on binding to B7 costimulators include the PI-3 kinase/AKT and MAP-kinase pathways.
CD28 engagement likely amplifies some TCR signaling pathways triggered by antigen recognition and induces other signals complementary to TCR signals.
CD28 signals increase the production of survival factors, IL-2, and cell cycle inducers, promoting survival and proliferation of activated T cells and their differentiation into effector and memory cells.
Metabolic Changes in Lymphocyte Activation
Lymphocyte activation is associated with profound changes in cellular metabolism.
Naive (resting) T cells take up low levels of glucose and use oxidative phosphorylation to generate energy in the form of adenosine triphosphate (ATP).
Upon activation, glucose uptake increases markedly, and cells switch to aerobic glycolysis.
This process generates less ATP but facilitates the synthesis of more amino acids, lipids, and other molecules that provide building blocks for organelles and daughter cells.
Activated T cells can more efficiently manufacture cellular constituents needed for their rapid increase in size and producing daughter cells.
Functional Responses of T Lymphocytes to Antigen and Costimulation
Recognition of antigen and costimulators by naive T cells initiates responses that culminate in the expansion of antigen-specific clones of lymphocytes and the differentiation of naive T cells into effector and memory cells.
Many changes in T cells are mediated by cytokines secreted by the T cells, acting on themselves and other cells involved in immune defenses.
Secretion of Cytokines and Expression of Cytokine Receptors
In response to antigen and costimulators, T lymphocytes, especially CD4+ T cells, rapidly secrete the cytokine IL-2.
In adaptive immunity, cytokines are mainly secreted by CD4+ T cells.
Most adaptive immunity cytokines, other than IL-2, are produced by effector T cells and have diverse roles in host defense.
IL-2 is produced within 1 to 2 hours after antigen stimulation of CD4+ T cells.
Activation also transiently increases the expression of the high-affinity IL-2 receptor, enhancing the ability of T cells to bind and respond to IL-2.
Interleukin-2 (IL-2) and T Cell Function
The receptor for IL-2 is a three-chain molecule; naive T cells express β and γ chains, constituting the low-affinity receptor, but do not express the α chain (CD25) for high-affinity binding.
Within hours after activation, T cells produce the α chain of the receptor, enabling the complete IL-2 receptor to bind IL-2 strongly.
IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on the same T cells, an example of autocrine cytokine action.
IL-2 stimulates the survival and proliferation of T cells, increasing the number of antigen-specific T cells and was originally called T cell growth factor.
Regulatory T cells constitutively express the high-affinity IL-2 receptor, making them very sensitive to IL-2, which is essential for their maintenance and for controlling immune responses.
Activated CD8+ T cells and natural killer (NK) cells express the low-affinity βγ receptor and respond to higher concentrations of IL-2.
Clonal Expansion
T lymphocytes activated by antigen and costimulation begin to proliferate within 1 or 2 days, resulting in expansion of antigen-specific clones
This expansion provides a large pool of antigen-specific lymphocytes for effector cell generation to combat infection.
The magnitude of clonal expansion is significant, especially for CD8+ T cells.
Before infection, the frequency of CD8+ T cells specific for any one microbial protein antigen is in the range of 1 in 105 to 1 in 106 lymphocytes in the body.
At the peak of some viral infections, as many as 10% to 20% of all the lymphocytes in the lymphoid organs may be specific for that virus.
This means that the numbers of cells in antigen-specific clones have increased by more than 10,000-fold, with an estimated doubling time of approximately 6 hours.
T Cell Proliferation Dynamics
The enormous expansion of T cells specific for a microbe is not accompanied by a detectable increase in the numbers of bystander cells that do not recognize that microbe.
The magnitude of expansion of CD4+ T cells appears to be 100-fold to 1000-fold less than that of CD8+ cells.
This difference may reflect differences in the functions of the two types of T cells since CD8+ CTLs are effector cells that kill infected and tumor cells by direct contact, and many CTLs may be needed to kill large numbers of infected or tumor cells.
In contrast, each CD4+ effector cell secretes cytokines that activate numerous other effector cells, so a relatively small number of cytokine producers may be sufficient.
Differentiation of Naive T Cells into Effector Cells
Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
Differentiation is the result of changes in gene expression, such as the activation of genes encoding cytokines (in CD4+ T cells) or cytotoxic proteins (in CD8+ CTLs).
It begins in concert with clonal expansion, and differentiated effector cells appear within 3 or 4 days after exposure to microbes.
Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines such as Th1, Th2, and Th17.
Many of these cells leave the secondary lymphoid organs where they are generated and migrate to sites of infection, where their cytokines recruit other leukocytes that destroy or help contain the inciting infectious agents.
Other differentiated CD4+ T cells remain in the lymphoid organs and migrate into lymphoid follicles, where they further differentiate into T follicular helper (Tfh) cells and help B lymphocytes to produce high-affinity antibodies.
Effector cells of the CD8+ lineage acquire the ability to kill infected and tumor cells.
Development of Memory T Lymphocytes
A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
These cells form a pool of lymphocytes that are induced by microbes and are ready to respond rapidly if the microbe returns.
The factors that determine whether the progeny of antigen-stimulated lymphocytes will differentiate into effector cells or memory cells are not well defined.
Memory Cells:
Survival: Memory cells survive even after the infection is eradicated and antigen is no longer present. Certain cytokines, including IL-7 and IL-15, may serve to keep memory cells alive and cycling slowly.
Rapid Response: Memory T cells can be rapidly induced to produce cytokines or kill infected cells on encountering the antigen that they recognize. They respond much more rapidly than naive lymphocytes and produce larger (secondary) responses than those of newly activated T cells (primary responses).
Location: Memory T cells are found in secondary lymphoid organs, in various peripheral tissues, especially mucosa and skin, and in the circulation.
subtypes include central memory cells (populate lymphoid organs), effector memory cells (localize in mucosal and other peripheral tissues), and tissue-resident memory cells (reside in the skin and mucosal tissues).
Memory T cells likely can be activated in both lymphoid and nonlymphoid tissues, and their activation, unlike that of naive T cells, does not require high levels of costimulation or antigen presentation by dendritic cells.
Regulation of T Cell Responses by Inhibitory Receptors (Coinhibitors)
Immune responses are influenced by a balance between engagement of activating and inhibitory receptors and In T cells, the main activating receptors are the TCR complex and costimulatory receptors such as CD28, and the best-defined inhibitory receptors, also called coinhibitors, are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1).
The functions and mechanisms of action of these inhibitors are complementary
CTLA-4
CTLA-4 is a B7-binding protein expressed transiently on activated CD4+ T cells and constitutively on regulatory T cells (discussed in Chapter 9).
It functions to suppress the activation of responding T cells and works by blocking and removing B7 molecules from the surface of APCs, thus reducing costimulation by CD28 and preventing the activation of T cells.
CTLA-4 has a higher affinity for B7 molecules than does CD28, so it binds B7 tightly and prevents the binding of CD28.
This competition is especially effective when B7 levels are low (as would be expected when APCs are only displaying self and maybe some tumor antigens but not microbial antigens); in these situations, the receptor that is preferentially engaged is the high-affinity blocking receptor CTLA-4.
PD-1
PD-1 is expressed on CD8+ and CD4+ T cells after antigen stimulation.
Its cytoplasmic tail has inhibitory signaling motifs with tyrosine residues that are phosphorylated upon recognition of its ligands PD-L1 or PD-L2, which are homologous to the B7 molecules described earlier.
Once phosphorylated, the tyrosines in the PD-1 tail bind a tyrosine phosphatase that inhibits kinase-dependent activating signals from CD28 and the TCR complex.
Expression of PD-1 ligands is increased by cytokines produced during prolonged inflammation, making this pathway most active in situations of chronic or repeated antigenic stimulation.
Its major function may be to limit responses to infections, such as viral infections, enough to prevent the immunopathology that often results from strong T cell activation.
Therapeutic Applications of Inhibitory Receptors
Treatment of cancer patients with antibodies that block these receptors, a form of cancer immunotherapy called checkpoint blockade.
Such treatment leads to enhanced antitumor immune responses and tumor regression in many patients.
However, patients treated with antibodies to inhibitory receptors often develop autoimmune reactions, demonstrating that the inhibitory receptors are constantly functioning to keep autoreactive T cells in check.
Several receptors on T cells other than CTLA-4 and PD-1 have been shown to inhibit immune responses and are currently being tested as targets of checkpoint blockade therapy.
Migration of T Lymphocytes in Cell-Mediated Immune Reactions
T cell responses are initiated primarily in secondary lymphoid organs.
The effector phase occurs mainly in peripheral tissue sites of infection.
T cells at different stages of their lives have to migrate in different ways.
Naive T cells migrate between blood and secondary lymphoid organs until they encounter dendritic cells within the lymphoid organ that display the antigens the T cells recognize.
After naive T cells are activated and differentiate into effector cells, these cells migrate back to the sites of infection, where they function to kill microbes.
Molecules Controlling T Cell Migration
The migration of naive and effector T cells is controlled by three families of proteins—selectins, integrins, and chemokines.
The routes of migration of naive and effector T cells differ significantly because of selective expression of different adhesion molecules and chemokine receptors.
Naive T cells express the adhesion molecule L-selectin (CD62L) and the chemokine receptor CCR7, which mediate the selective migration of the naive cells into lymph nodes through specialized blood vessels called high endothelial venules (HEVs).
HEVs are located in the T cell zones of lymph nodes and mucosal lymphoid tissues and are lined by specialized endothelial cells, which express carbohydrate ligands that bind L-selectin.