5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate || U TO Date7 Official reprint from UpToDate® p www.uptodate.com © 2024 UpToDate, Inc and/or its affiliates All Rights Reserved ® The adaptive cellular immune response: T cells and cytokines AUTHOR: Jennifer Heimall, MD SECTION EDITOR: Luigi D Notarangelo, MD DEPUTY EDITOR: Elizabeth TePas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Apr 2024 This topic last updated: Jan 30, 2023 INTRODUCTION T cells regulate the activities cells participating in immune responses They provide help for antibody production by B cells, and they are also the effectors of antigen-specific cell-mediated immunity (CMI) CMI is important in the elimination of intracellular infections (eg, viruses, mycobacteria, and some bacteria) and aberrantly differentiating cells (eg, neoplasms) CMI also destroys allogeneic cells (graft rejection) In addition, it is involved in cellular autoimmune responses, as well as type IV allergic reactions to drugs and contact dermatitis Furthermore, T cells activate innate immune cells such as phagocytic cells to become more effective at killing other types of pathogens such as fungi (See "Transplantation immunobiology" and "Overview of autoimmunity" and "Drug hypersensitivity: Classification and clinical features", section on ‘Type IV reactions' and "Overview of dermatitis (eczematous dermatoses)", section on ‘Allergic contact dermatitis'.) T cell receptors (TCRs), in contrast to immunoglobulins, exist only as multimeric membrane- bound complexes and are not secreted intact in soluble form Also unlike immunoglobulins, TCRs recognize fragments (peptides) of protein or glycoprotein antigens in complexes with major histocompatibility molecules on the surfaces of antigen-presenting cells (APCs, also called accessory cells) or on targets of cytotoxicity Note the distinction between the processed antigen (peptide) eliciting a response and the major histocompatibility complex (MHC) antigen with which it becomes associated to stimulate peptide-specific T cells (See "T-B-NK+ SCID: https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 1/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate Pathogenesis, clinical manifestations, and diagnosis", section on "T cell receptor generation' and "Normal B and T lymphocyte development”.) The cellular interactions that form the basis of CMI are discussed in this topic review Related topics and T cell help for antibody production are discussed separately (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation’ and "Normal B and T lymphocyte development" and "The adaptive humoral immune response".) ANTIGEN-PRESENTING CELLS T cell responses are initiated by antigen-presenting cells (APCs), which are reviewed briefly here and discussed in greater detail elsewhere (See "Antigen-presenting cells".) Dendritic cells (DCs) are the predominant class of "professional" APCs [1] The main subtypes include plasmacytoid DCs (pDCs) and conventional DCs (cDCs) These are further divided into additional subtypes that have distinct surface marker expression, morphology, tissue distribution, and cytokine production These different types of DCs lead to distinct pathways of T cell stimulation Monocytes/macrophages may also exert some APC activity, and monocytes may differentiate into DCs Only APCs constitutively express major histocompatibility complex (MHC) class II molecules (which are required for activation of CD4+ T cells) and display the necessary costimulatory signals The great majority of somatic cells express MHC class I molecules and can serve as targets of CD8+ cytotoxic T cells B cells express MHC class II molecules, which are required to receive T cell help (see "The adaptive humoral immune response") Although they are not strong enough to activate resting naive T cells, B cells may stimulate memory T cells (See ‘Memory T cells' below.) DCs use a system of pattern recognition receptors, such as "Toll-like" receptors (TLRs), that bind to a variety of microbial products, including bacterial lipopolysaccharide, flagellin, and lipopeptides These receptors stimulate development and migration of immature DCs in the periphery Under the influence of cytokines and chemokines, DCs mature and migrate into the secondary lymphoid tissues where they interact with T and B cells in T zones of the lymph nodes, Peyer patches, and the spleen Cysteine-cysteine motif chemokine receptor (CCR) 7 and cysteine-X-cysteine motif receptor (CXCR) 5 both act to assist DC, T, and B cell trafficking to lymphoid tissues [2] (See "Toll-like receptors: Roles in disease and therapy".) https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 2/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate DCs are highly active in processing and presenting antigen to T cells Antigen is taken up via several means (macropinocytosis, in immune complexes via immunoglobulin G [IgG] Fc receptors, etc) The antigen is then degraded, and peptides are loaded onto MHC class I or class II molecules Intracellular-derived antigens (intracellular self-proteins or products of organisms that replicate intracellularly) are predominantly presented via MHC class I molecules and extracellular antigens mainly via MHC class II molecules However, there is significant overlap in these pathways CYTOKINES Immune cells produce a variety of products that allow them to communicate with each other and orchestrate an explosive, yet self-limited attack Cytokines are hormone-like glycoproteins that enable immune cells to communicate with one another by either direct contact or through the secretion of soluble mediators They play an integral role in the initiation, perpetuation, and subsequent downregulation of the immune response (_ table 1) Direct cell-cell contact regulates immune function of adjacent cells by a variety of mechanisms, including membrane-bound cytokines such as tumor necrosis factor (TNF) alpha In contrast, release of soluble mediators into the environment permits cells to exert influence at a distant site within the tissue In some cases, cytokines can even reach distant cells in other organs via the peripheral circulation For instance, interleukin (IL) 6 produced at a local inflammatory site can enhance liver acute-phase protein production Soluble cytokines bind to a specific receptor on the surface of target cells and transduce a signal that alters cellular function The migration of immune cells is accomplished by a highly redundant family of cytokines known as chemokines These factors, which are classified by their amino acid sequence and their inflammatory and immune regulatory homeostatic roles, bind to specific surface receptors that induce cells to migrate into tissues [3] However, there is plasticity to the relationship of chemokines binding to their receptors such that loss of a single chemokine receptor does not lead to a profound loss in the ability of immune cells to migrate and carry out their intended functions [4] The roles of chemokines include induction of cellular migration, local cellular activation and survival, and homeostatic regulation of immune cells T CELL ACTIVATION AND FUNCTIONS T cell receptor-CD3 complex — The T cell receptor (TCR) alpha-beta (TCR2) or gamma-delta (TCR1) heterodimer is noncovalently associated with the CD3 complex on the cell membrane https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 3/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate There are four types of CD3 subunits: gamma, delta, epsilon, and zeta CD3 complex is most comprised of gamma-epsilon and delta-epsilon heterodimers and a zeta homodimer in of the cells The gamma and delta chains of CD3 are distinct from the gamma and delta forms TCR itself The CD3 complex is expressed on all T cells The complex has a critical role in transducing a signal of TCR contact across the lymphocyte membrane (_figure 1) The interaction of the TCR with a complementary complex of peptide plus major histocompatibility complex (peptide-MHC) forms the basis of the antigen specificity ofT cell activation by antigen- presenting cells (APCs) and target cell recognition in cell-mediated immunity (CMI) (See "T-B- NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.) T cell accessory molecules — T cells are categorized based upon cell surface expression of one of two coreceptor molecules, either cluster of differentiation (CD) 4 or CD8 CD4 and CD8 have great importance for T cell development and for antigen recognition and activation of mature T cells (see "Normal B and T lymphocyte development") CD4+ cells recognize antigen presented by a MHC class II, while CD8+ cells recognize antigen presented by an MHC class I There are a host of additional cell surface molecules that play roles in T cell interactions with other cells including T cell activation by APCs, T cell regulation of other T cells and B cells, and cytotoxic T cell killing Some of these are adhesion molecules, others are mainly transducers of activating or inhibitory signals, and several have multiple functions Some of these T cell accessory molecules are summarized in the table( table 2) T cell circulation — Upon their egress from the thymus, naive T cells circulate throughout the body in both the blood and lymph fluids Naive T cells circulating through secondary lymphoid tissues, such as spleen, lymph nodes, and Peyer's patches in the intestine, encounter dendritic cells (DCs) that have similarly migrated to these tissues to present antigens The naive T cells "scan" the antigens presented by the DCs When an antigen-MHC complex of suitable affinity is identified, the naive T cells are activated [5] Since naive T cells continually recirculate through the blood, spleen, lymph, lymph nodes, and other tissues [6] throughout the body, they are able to sample antigens derived from a wide range of distinct anatomic sites Following engagement of the appropriate complementary complex, the activated naive T cells proliferate Activated T cells also migrate toward the periphery of the T cell-rich areas in the secondary lymphoid organs to facilitate contact with the B cell-rich areas This permits interactions with antigen-specific B cells, thereby providing T cell help for antibody production (See "The adaptive humoral immune response") https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 4/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate Activated naive T cells may either become effector T cells, which are then able to further differentiate to memory cells, or they may directly differentiate to become memory T cells Most effector T cells will then migrate from the lymphoid organs into the peripheral circulation and tissues This permits effector T cells to reach sites of infection T cell activation via the two-signal model — The paradigm for T cell activation is the so-called "two-signal" model( figure 1) All of the cell surface molecules listed in the table may play a role in T cell activation( table 2) During intercellular contact, many of these molecules interact with cytoskeletal elements and are organized into specific regions within the zone of contact named the "immunologic synapse" ( figure 1) [7] The two-signal model of T cell activation includes the following: ¢ Signal 1 derives from contact of TCR-CD3 with a peptide-MHC complex It is possible, particularly where agonist (foreign) peptide- MHC complexes occur at very low density on the APC surface, that endogenous (self) peptide- MHC complexes also participate in the initiation of the immunologic synapse [8] ¢ Signal 2 derives from costimulatory pathways A tremendously complex cascade of events within the cytoplasm ensues upon receptor and costimulator ligation( figure 2) [9] TCR signaling is discussed in detail separately (See "T cell receptor signaling".) Binding of TCR-CD3 without engaging any costimulating molecules leads to a state of anergy (unresponsiveness or refractoriness to activation) and possibly even to deletion by apoptosis (death) [10] This may be an important mechanism in T cell tolerance (See "Apoptosis and autoimmune disease".) The mechanism by which costimulation leads to activation rather than anergy is unknown The interaction between CD28 expressed on T cells and CD80 and CD86 (B7-1 and B7-2) expressed on APCs is a very potent costimulatory system [10] T cells express CD154 (CD40 ligand, CD40L) following activation via the TCR CD40L binds to CD40 expressed on the APC surface and induces expression of CD80 and CD86 by the APC Binding of these to CD28 on a resting T cell will not activate the cell, but, once aT cell has been "primed" by antigen exposure, ligation of CD28 can trigger production of interleukin (IL) 2 and cellular proliferation The simultaneous production of the cytokine IL-2 and a component of its high-affinity receptor (IL-2R-alpha or CD25) initiates a positive feedback loop that is important for T cell proliferation https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 5/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate Inducible T cell costimulator (ICOS) is a CD28 homolog that is inducibly expressed on activated T cells [10] Interaction with ICOS ligand (ICOS-L, a B7 homolog) may augment T cell activation However, ICOS also appears to have other roles in modulating IL-10 production by regulatory T cells (Tregs) and inhibiting development ofT helper type 17 (Th17) cells (See 'Treg' below and 'Th17' below.) A wide variety of additional signaling molecules expressed on T cells and APCs influence the activation or suppression and differentiation ofT cells into effector/memory or regulatory cells [10] CD4+ T cell activation — The following sequence of events takes place during activation of CD4+ T cells: ¢ DCs capture and process antigen from peripheral sites They then migrate into lymph nodes and develop into mature APCs ¢ Naive T cells "scan" DCs with their TCR, looking for complementary peptide-MHC e Antigen recognition triggers a complex cascade of intercellular membrane glycoprotein contacts and intracellular biochemical signals ¢ The T cell-APC (or other cell) interaction is modulated by alterations in the expression of surface molecules and cytokine secretion by both cells ¢ Specific characteristics of the cytokine milieu and the combination of signals results in either activation or tolerization of the T cell It also determines the effector phenotype of an activated cell ¢ The activated/effector T cell may then migrate into peripheral tissues or undergo further interactions with other cells (eg, B cells) within lymphoid tissues Cytokine profiles and functions of CD4+ T helper cell subsets — Activated CD4+ T cells are subdivided into distinct functional categories depending upon the profile of secreted cytokines( figure3and table3and table 1) [11] The conditions under which aT cell is stimulated have great influence on the functional phenotype of the activated cell The route by which antigens enter the body (eg, skin, gut, etc), the form of the antigen (inert molecules, living microorganisms), and the amount of antigen are all important factors that impact the differentiation to these functional T cell subsets At the cellular level during T cell stimulation, the degree of TCR occupancy, the activity of various costimulatory pathways, and the presence of certain cytokines all influence the https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 6/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate phenotype of activated cells As examples, IL-12 and interferon (IFN) gamma are the cytokines T helper that drive T helper type 1 (Th1) cell development, while IL-4 is critical for determining type 2 (Th2) development(_ table 1) These helper T cell subpopulations are not easily distinguished with respect to surface markers Thus, they are usually identified by their cytokine production In general, each of these cytokine production subtypes does not amount to more than 2 to 5 percent of the T cells in circulation, usually less These proportions are highly variable and depend upon many factors such as chronic and/or acute infection and inflammation, the genetic makeup of the individual, and modifying environmental factors Proportions of one or more subsets may be higher in lymphoid or other tissues, again depending upon the specific tissue and ongoing immunologic processes (See "Normal B and T lymphocyte development”.) Several subsets have been distinguished for CD4+ T cells These can be grouped into those associated with effector activities (Th1, Th2, Th9, Th17, Th22, and follicular helper T cells [Tfh]) and those with regulatory activities (natural regulatory T cell [nTreg], induced regulatory T cell [iTreg (type 1 regulatory T cell [Tr1])], Th3)(_—s figure 3) [11] The Th1 and Th2 patterns have been most extensively studied These patterns are to some degree mutually exclusive, as one pattern often clearly predominates in the context of a particular immune response Th1 — T helper type 1 (Th1) responses promote production of opsonizing antibodies (eg, IgG1) and induction of cellular cytotoxicity and macrophage activation Th1 cells secrete IFN-gamma and IL-2 but not IL-4 They activate macrophages and help in the eradication of intracellular micro-organisms, such as mycobacteria and viruses Th1 cells also promote cytotoxic T cell development and delayed-type hypersensitivity (DTH) reactions Hence, Th1 cells are proinflammatory and may be involved in the pathogenesis and maintenance of some autoimmune diseases Th1 cells express both chains of the IL-12 receptor (IL-12-R-beta-1 and IL-12-R-beta-2) [12,13], as well as cysteine-X-cysteine motif receptor (CXCR) 3 and cysteine-cysteine motif chemokine receptor 5 (CCR5) [12,14-16] Th1 responses are promoted by local release of the IL-12 superfamily of cytokines including IL-27, IL-23, and IL-12 IL-12 may favor IFN-gamma release, whereas IL-23 may favor IL-17 release These responses are further enhanced by IL-15 and IL-18 production by DCs and macrophages T-bet promotes Th1 development by direct induction of IFN-gamma and IL-12-R-beta-2 chain gene transcription [17,18] In addition, T-bet appears to inhibit IL-4, IL-5, and IL-17 secretion T- bet may also inhibit Th2 differentiation by preventing GATA-binding protein 3 (GATA3) from interacting with its target DNA [19] https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 7/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate Th2 — T helper type 2 (Th2) cells produce IL-4, IL-5, IL-13, and IL-10 but not IL-2 or IFN- gamma By virtue of their IL-4 and IL-13 secretion, they are important in the promotion of immunoglobulin E (IgE) synthesis and via IL-5 stimulate eosinophil development They help mediate immunity against parasitic infestations, particularly helminths, and are pivotal in the development of allergy and asthma [20-22] Th2 cells express IL-12-R-beta-1 [12,13] and IL-4 receptors [23] CCR3, CCR8, and CCR10 are also expressed by Th2 cells [12,14-16] Th2 responses are favored by synergistic local production of IL-4, IL-33, and IL-18 GATA3 is pivotal for Th2 maturation [17,18] Th9 — T helper type 9 (Th9) cells produce IL-9 and IL-10 Th9 development from naive Th cells is mediated by transcription factors signal transducer and activator of transcription (STAT) 6 and PU.1 (binds to a purine-rich DNA sequence called the PU-box) [24,25] in the presence of transforming growth factor (TGF) beta, IL-2, and IL-4 These cells have a role in antitumor immunity, allergy, and autoimmune disease [26] They are also thought to be important in resistance to parasites and may be involved in asthma and other allergic disease [27,28] PU.1 has a negative effect on the expression of CD40L in CD4 cells and downregulates IL-21 expression as well, leading to decreased germinal cell B cell expansion and reduced IgG production [29] Th17 — T helper type 17 (Th17) cells secrete IL-17A, which induces production of proinflammatory cytokines (IL-17F, IL-22, IL-26) and chemokines (CCL20) and recruits neutrophils [12] Th17 cells appear to be involved in the early response to numerous extracellular pathogens, including bacteria and fungi, and play an important role in driving chronic inflammatory responses in chronic infection, allergy, and autoimmunity [30,31] They may also play a role in the neutrophil, rather than eosinophil, predominant forms of asthma [32] Th17 cells express only IL-12-R-beta-1 [12,13] Th17 cells express the IL-23 receptor, a heterodimer comprised of IL-12-R-beta-1 and a unique IL-23-R chain, in addition to receptors for IL-6, IL-21, and TGF-beta [12,33] CCR2 and CCR6 are expressed by Th17 cells [12,14-16] Retinoid-related orphan receptor gamma t (RORgT) is critical for Th17 maturation [17,18] Th22 — T helper type 22 (Th22) cell production is upregulated by RORgT and downregulated by Tbet Th22 cells are a major source of IL-22, although this cytokine is also produced by Th17 cells [34] When IL-22 is cosecreted with IL-17, the effect tends toward more proinflammatory outcomes, particularly in psoriasis In asthma and atopic dermatitis, increased frequency of IL-22 cells is associated with increased disease severity Th22 cells can also have a protective role in mucosal immunity [35] https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 8/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate Tfh — T follicular helper (Tfh) cells are preponderant in germinal centers in secondary lymphoid tissues where they have a prominent role in providing help to B cells for high-affinity antibody production [36-38] IL-12 may be crucial to Tfh development [39] Circulating Tfh express high levels of the chemokine receptor CXCR5 [40] Naive CD4 T cells differentiate to Tfh cells when the transcription factor B cell lymphoma 6 protein (BCL6) is expressed along with high levels of CXCR5, which allows these T cells to migrate to and reside in the germinal centers of lymph nodes [41] Tfh resident in lymph node germinal centers can be characterized by the surface markers CCR7!°PSGL1!°CXCR5", Pp-1", ICOS" [40] The development of Tfh cells is inhibited by B lymphocyte-induced maturation protein 1 (Blimp-1) and STATS, IL-12, IL-23 and TGF-beta are the initiating cytokines for Tfh differentiation [39] IL-1 and IL-6 signaling through STATS3 are also important in the differentiation of Tfh In the presence of appropriate cytokines and B cell interactions, Tfh cells can differentiate into Th1-like, Th2-like, or Th17-like Tfh cells [36] Treg — T regulatory (Treg) cells are central to the establishment and maintenance of peripheral tolerance They play a principal role in negative regulation (suppression) of the immune response Treg cells typically comprise 1 to 2 percent of the total CD4 population, but overall are critically responsible for the suppression of effector CD4 T cell effects through contact inhibition of activity between APC and effector T cells or direct cytotoxicity Development of nTregs is mediated by the transcription factor forknead box P3 (Foxp3), which leads to surface expression of cytotoxic T lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), killer cell lectin-like receptor G1 (KLRG1), CD25, and Blimp-1 Treg cells also commonly express CD134 (OX40), CD27, and CD62-L and secrete TGF- beta, IL-10, and also IL-35, a novel member of the IL-12 superfamily [42] Their effector function is often dependent upon cell contact-mediated cellular suppression (See 'Suppression' below.) iTreg — Induced T regulatory (iTreg) cells can be induced in the periphery after antigen priming in the presence of retinoic acid and TGF-beta Th3 — T helper type 3 (Th3) cells are important in mucosal tolerance induction and may promote development and/or maintenance of induced Treg cells [43] CD8+ T cell activation — Cytotoxic T cells (cytotoxic T lymphocytes [CTLs]), the majority of which express the CD8 coreceptor for MHC class I, are also activated by professional APCs in lymphoid tissues, as are CD4-bearing cells However, the APC must first be activated by contact with an antigen-specific CD4+ T cell before it is capable of inducing a naive CD8+ cell to become a full-fledged effector (cytotoxic) T cell [44] Direct CD4+ T cell help may also be required for https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respon 9/45 5/15/24, 10:37 AM The adaptive cellular immune response: T cells and cytokines - UpToDate primary CD8+ T cell responses in the face of viral challenge, in particular by increasing IFN- gamma and Fas ligand (FasL) expression [44,45] As mentioned above, virtually all nucleated cells process cytoplasmic molecules and present them on their surfaces in association with MHC class I molecules (see 'Antigen-presenting cells' above) Thus, antigens derived from pathogens that replicate intracellularly are presented in this manner Professional APCs may also present antigens internalized by phagocytosis via MHC class I molecules [1] The degree to which MHC molecules bearing antigen cluster on the cell surface appears to affect the sensitivity of T cell recognition [46] Cytotoxic T lymphocyte function — After acquiring effector function in lymphoid tissues, cytotoxic cells circulate in the periphery, "searching" for infected cells to kill The first step in lysis is membrane contact between the cytotoxic and target cells presenting antigens specific to the TCR, forming the immunologic synapse This contact is mediated by the TCR/CD8-MHC class I interaction, as well as by several T cell/target cell adhesion molecule interactions (eg, CD2 with CD58, CD11a/CD18 with CD54CD54 and others) [47] Cytotoxicity occurs via two principal mechanisms: granule exocytosis and expression of FasL In addition to these cytotoxic mechanisms, CTLs also secrete a variety of cytokines, such as IFN- gamma and TNF, that may directly damage target cells or inhibit microbial replication [47] They also recruit and modulate additional inflammatory effector cells, such as macrophages Natural killer (NK) cells express a cytotoxicity activating molecule called natural killer group 2 D (NKG2D or killer cell lectin-like receptor, subfamily K, member 1 [KLRK1]) Two ligands for NKG2D are MHC class I-like molecules MHC class I chain-related gene A (MICA) and ULBP4 (binding protein 4 for the cytomegalovirus-encoded glycoprotein UL16) CTLs also express NKG2D, and cytotoxicity of these cells can also be promoted by interaction with MICA and ULBP4 [48] The latent membrane protein 2A (LMP2A) on the surface of Epstein-Barr virus (EBV) transformed cells can reduce expression of or interfere with the interaction of MICA and ULBP4 with NKG2D and inhibit CTL recognition of EBV transformed B cells A single CTL may "recycle" and lyse several target cells without itself suffering damage It is unclear how CTLs are protected from the destructive potential of the molecules they discharge CTLs are not themselves immune to lysis, since they may themselves be the targets of other cytotoxic cells Granule exocytosis — Following contact with the target cell, lytic granules within the CTL gather near the immunologic synapse (a process called "polarization") The membranes of the granules fuse with the CTL membrane and release their contents directly adjacent to the target cell CTL granules contain a variety of substances that enter the target cell and initiate https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines/print?search=The adaptive cellular immune respo 10/45