Essential Principles of Immunology
Differentiating self from nonself is a hallmark of the immune response
The immune system is a network of tissues, cells, and signaling molecules that work to protect the body by recognizing and attacking foreign cells, while seeking to minimize the damage to healthy cells.1,2 This ability to differentiate self (the body’s own normal cells) from nonself (abnormal/foreign cells) is a hallmark of the immune response.2,3
The capacity of the immune system to recognize self-antigens and accept the presence of normal cells is known as self-tolerance.2 When self-tolerance fails, it can result in autoimmunity, whereby the immune system may fail to discriminate self from nonself and attack normal cells.4
To prevent autoimmunity, immune cells learn to overlook self-antigens, both during their maturation (central tolerance) and as they circulate in peripheral tissue (peripheral tolerance).2 Most self-reactive T cells are eliminated early in their development; however, peripheral tolerance exists to prevent recognition of self-antigens that may not have been encountered during maturation. Immune checkpoint pathway interaction is one mechanism of peripheral tolerance.2,5
Antigens, small molecules, or peptides capable of eliciting an immune response are key elements in this process of distinguishing self from nonself.1 Antigens serve as labels that enable the immune system to distinguish between a normal interaction (self) and an encounter with a foreign threat (nonself).1 Inactive T cells search for nonself antigens by transiently binding to antigens presented by major histocompatibility complexes on antigen-presenting cells (APCs).6 Recognition of nonself antigens activates cytotoxic T cells.1 Although originating from normal cells, tumor antigens can be recognized as nonself. Neoantigens, a type of tumor antigen, arise from normal
Both innate and adaptive immune systems can differentiate self
Innate immune response is rapid, while adaptive immune response is not as immediate but can produce a durable response through the development of memory cells, including memory
T cells.1,8 Chronic exposure to a nonself antigen can promote the accumulation of memory T cells.8 Innate and adaptive immunity are activated through distinct and often complementary mechanisms that deploy different effector cells to attack and destroy abnormal/foreign cells such as cancer.1
Innate immunity, the body’s first line of defense, is non-specific, short-lived, and activates independently of antigens, allowing for the rapid identification and elimination of foreign threats.1 Numerous cell types are involved with the innate immune response, including macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells, and T cells.1 The primary effector cells of the innate immune response, NK cells, continually scan the body for abnormal cells to attack.1-3
Upon recognition of a tumor cell through engagement of an activating receptor, NK cells proliferate and rapidly kill their target.3,4 Following tumor-cell death, the NK cells move on in search of other targets.3 In death, tumor cells can release tumor antigens and other factors.5-7
NK cells do not rely on antigens to identify nonself invaders.1 Instead, NK cells express receptors that interact with activating and inhibitory signals from normal and abnormal cells. The balance of these signals determines NK-cell behavior.8 By engaging inhibitory receptors on NK cells, normal cells are able to identify themselves as self and protect against an immune attack.9 In contrast, tumor cells express ligands that are not typical of normal cells.2,10 When the activating signals of tumor ligands prevail, they stimulate NK-cell antitumor immunity.9,11
Adaptive immunity is antigen-dependent, antigen-specific, and able to produce a durable response.1 In cancer, tumor antigens such as those released by tumor-cell death are derived from mutated or modified
Cytotoxic T cells, the primary effector cells of the adaptive immune response, are activated by nonself antigens, including tumor antigens, in secondary lymphoid organs such as lymph nodes.1,15 Once activated, cytotoxic T cells proliferate, migrate to the location of the antigen, and infiltrate it, directly initiating cell death.16 Unlike the innate immune response, adaptive immunity is not immediate, but can be sustained through a memory-cell response, which includes memory T cells.1,17
Antigen-presenting cells (APCs) are central messengers between innate and adaptive immunity
Tumor-cell death allows the release of certain molecules, such as adenosine triphosphate (ATP) and tumor DNA, that can cause the activation of APCs, including dendritic cells.1,2 APCs act as messengers between the innate and adaptive immune response.3
Inflammatory signals such as ATP can trigger the formation of an inflammasome within the APC.1,2 Inflammasomes are protein complexes that initiate an inflammatory immune response, recruitment, and response of innate immune cells by converting proinflammatory cytokines from a dormant to an active state.4 Once activated, these cytokines are released by APCs to increase the antitumor activity of NK cells and T cells.1,4,5
Tumor DNA can be detected within the APC by special sensors.6 These sensors stimulate the APC to engulf proteins released during tumor-cell death and process them into antigens.2,7,8 One of the primary functions of APCs is to present these antigens to inactive T cells.8 The first presentation of an antigen to an inactive T cell leads to its activation and proliferation. This process, known as T-cell priming, initiates the adaptive immune response.8
APCs express cell-surface proteins called major histocompatibility complexes (MHCs), which present fragments of processed antigen to the T cell.3 T-cell receptors (TCRs) on the surface of inactive T cells recognize the presented MHC antigen complex, which initiates activation and proliferation of cytotoxic T cells.3,9
T cells can destroy tumor cells and provide long-term immunity
Antigen recognition later causes activated T cells to migrate to and infiltrate the tumor site. Following infiltration into the tumor, cytotoxic T cells release secreted factors capable of promoting tumor-cell death.3 Early evidence suggests that a higher mutational burden may be associated with an increased likelihood of greater infiltration of cytotoxic T cells.10
Upon resolution of the immune attack, cytotoxic T cells either die or differentiate into memory T cells that persist long term.11 Memory T cells can re-recognize the antigen, providing the potential for a subsequent immune response.3,12
To identify and eliminate tumor cells, cytotoxic and memory T cells must be able to scan peripheral tissues in search of their unique activating antigen.1,2 To make this possible, activated T cells upregulate factors that enable them to recognize threats and migrate through blood vessel walls and into affected tissues.3,4 T-cell migration occurs across non-lymphoid tissues, with documented trafficking to particularly selective organs such as the eye and brain.5-11
Though the brain was once thought to be “immune privileged,” data suggest that the blood-brain barrier can be “leaky,” allowing for the movement of T cells and other immune molecules. This mobility enables activated cytotoxic T cells to patrol for antigens and infiltrate tumors in the brain.5,12 After the activated cytotoxic T-cell population diminishes, memory
T cells remain capable of trafficking to surrounding tissues in the event of antigen reoccurence.6
REFERENCES–Revealing the potential of I-O
1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011. doi:10.1186/1710-1492-7-S1-S1. 2. Van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science. 1998;280(5361):243-248. 3. Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 2004;22(6):1136-1151. 4. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Rev Immunol. 2004;22:531-562. 5. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer.
2012;12(4):252-264 6. Janeway Jr CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 5th ed. New York, NY: Garland Publishing; 2001. 7. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 8. Nikolich-Žugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512-522.
REFERENCES–NK cells are the main effectors of the innate immune system
1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011. doi:10.1186/1710-1492-7-S1-S1. 2. Cerwenka A, Bakker ABH, McClanahan T, et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity. 2000;12(6):721-727. 3. Vanherberghen B, Olofsson PE, Forslund E, et al. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood. 2013;121(8):1326-1334. 4. André P, Castriconi R, Espéli M, et al. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. Eur J Immunol.
2004;34(4):961-971. 5. Liu C, Lou Y, Lizée G, et al. Plasmacytoid dendritic cells induce NK
REFERENCES–APCs are central messengers between innate and adaptive immunity
1. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170-1178. 2. Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842. 3. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011.
REFERENCES–Activated and memory T cells can migrate throughout the body and recognize tumor antigens
1. Krummel MF, Bartumeus F, Gérard A. T cell migration, search strategies and mechanisms. Nat Rev Immunol. 2016;16(3):193-201. 2. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 3. Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168-7174. 4. Ferguson AR, Engelhard VH. CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J Immunol. 2010;184(8):4079-4086. 5. Masopust D, Vezys V, Usherwood EJ, et al. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol. 2004;172(8):4875-4882. 6. Woodland DL, Kohlmeier JE. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol. 2009;9(3):153-161. 7. Hirata T, Furie BC, Furie B. P-, E-, and L-selectin mediate migration of activated CD8+ T lymphocytes into inflamed skin. J Immunol. 2002;169(8):4307-4313. 8. Wekerle H, Sun D. Fragile privileges: autoimmunity in brain and eye. Acta Pharmacol Sin. 2010;31(9):1141-1148. 9. Agace WW.