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IMMUNO Midterms
IMMUNO Midterms
IMMUNO Midterms
Chapter I
Introduction to Immunology
This chapter will help the students to define and appreciate the significance/ importance of Immunology. The
basic terms that are used in this subject will be introduced to the students. Important people who contributed to the
field of immunology are acknowledged. The concept of immunity is introduced into this topic.
At the end of this chapter, the students will be able to define and appreciate the significance of Immunology.
They will be able to distinguish and familiarize themselves with the terms used in this subject. They will be able to
recognize the contributions of scientists involved in this field. They will be able to understand the basic concepts of
immunity
V. LESSON CONTENT
What is Immunology?
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all
organisms.
It deals with:
physiological functioning of the immune system in states of both health and disease
malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune
deficiency, transplant rejection)
the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and
in vivo Divisions/ Fields
◦ Histological examination of the immune system- histological characterization of different organs of the lymphoid system
◦ Classical immunology- ties in with the fields of epidemiology and medicine. It studies the relationship between the body
systems, pathogens and immunity
◦ Developmental immunology- concerns the immunological state of neonates
◦ Immunotherapy-The use of immune system components to treat a disease or disorder
◦ Diagnostic immunology- use of antigen and antibody as a tool in diagnostic techniques
◦ Reproductive immunology-devoted to the study of immunological aspects of the reproductive process including fetus
acceptance
◦ Clinical immunology- study of diseases caused by disorders of the immune system (failure, aberrant action, and
malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune
reactions play a part in the pathology and clinical features.
◦ Ecoimmunology, or ecological immunology, explores the relationship between the immune system of an
organism and its social, biotic and abiotic environment. More recent ecoimmunological research has focused on
host pathogen defences traditionally considered "non-immunological", such as pathogen avoidance, self-
medication, symbiont-mediated defenses, and fecundity trade-offs.
Behavioural immunity, a phrase coined by Mark Schaller, specifically refers to psychological pathogen avoidance
drivers, such as disgust aroused by stimuli encountered around pathogen-infected individuals, such as the smell of
vomit.] More broadly, "behavioural" ecological immunity has been demonstrated in multiple species.
History of Veterinary Immunology
◦ 1549 – The earliest account of inoculation of smallpox (variolation) occurs in Wan Quan's
◦ 1718 – Smallpox inoculation in Ottoman Empire realized by West. Lady Mary Wortley Montagu, the wife of the
British ambassador to Constantinople, observed the positive effects of variolation on the native population and had
the technique performed on her own children.
◦ 1796 – First demonstration of smallpox vaccination (Edward Jenner- Father of immunology)
◦ 1808 – 1813 - First experimental demonstration of the germ theory of disease by Agostino Bassi though he does not
formally propose the theory until 1844
◦ 1837 – Description of the role of microbes in putrefaction and fermentation (Theodore Schwann)
◦ 1850 – Demonstration of the contagious nature of puerperal fever (childbed fever) (Ignaz Semmelweis)
◦ 1857–1870 – Confirmation of the role of microbes in fermentation (Louis Pasteur)
◦ 1862 – Observation of Phagocytosis (Ernst Haeckel)
◦ 1867 – Aseptic practice in surgery using carbolic acid (Joseph Lister)
◦ 1876 – Demonstration that microbes can cause disease-anthrax (Robert Koch)
◦ 1877 –Discovery of Mast cells (Paul Ehrlich)
◦ 1878 – Confirmation and popularization of the germ theory of disease (Louis Pasteur)
◦ 1880 – 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines. Proposed
that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to make chicken
cholera and anthrax "vaccines" (Louis Pasteur)
◦ 1883 – 1905 – Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear
leukocytes) (Elie Metchnikoff)
◦ 1885 – Introduction of concept of a "therapeutic vaccination". Report of a live "attenuated" vaccine for rabies (Louis
Pasteur and Pierre Paul Émile Roux).
◦ 1888 – Identification of bacterial toxins (diphtheria bacillus) (Pierre Roux and Alexandre Yersin)
◦ 1888 – Bactericidal action of blood (George Nuttall)
◦ 1890 – Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of
immunity. (Emil von Behring) and (Kitasato Shibasaburō)
◦ 1891 – Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)
◦ 1893 – Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins" (William B. Coley) ◦ 1894 –
Bacteriolysis (Richard Pfeiffer)
◦ 1896 – An antibacterial, heat-labile serum component (complement) is described (Jules Bordet)
◦ 1900 – Antibody formation theory (Paul Ehrlich)
◦ 1901 – Blood groups (Karl Landsteiner)
◦ 1902 – Immediate hypersensitivity anaphylaxis (Paul Portier) and (Charles Richet)
◦ 1903 – Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus)
◦ 1903 – elucidation of the mechanism of Opsonization
◦ 1905 – "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick)
◦ 1909 – Paul Ehrlich proposes "immune surveillance" hypothesis of tumor recognition and eradication
◦ 1911 – 2nd demonstration of filterable agent that caused tumors (Peyton Rous)
◦ 1917 – Discovery of the Hapten (Karl Landsteiner)
◦ 1921 – Cutaneous allergic reactions (Otto Prausnitz and Heinz Küstner)
◦ 1924 – Discovery of the Reticuloendothelial system
◦ 1938 – Antigen-Antibody binding hypothesis (John Marrack)
◦ 1940 – Identification of the Rh antigens (Karl Landsteiner and Alexander Weiner)
◦ 1942 – Anaphylaxis (Karl Landsteiner and Merill Chase)
◦ 1942 – Adjuvants (Jules Freund and Katherine McDermott)
◦ 1944 – hypothesis of allograft rejection
◦ 1945 – Coombs test a.k.a. antiglobulin test (AGT)
◦ 1946 – Identification of mouse MHC (H2) by George Snell and Peter A. Gorer
◦ 1948 – Antibody production in plasma B cells
◦ 1949 – Growth of polio virus in tissue culture, neutralization with immune sera, and demonstration of attenuation of
neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins)
◦ 1951 – vaccine against yellow fever
◦ 1953 – Graft-versus-host disease
◦ 1953 – Validation of immunological tolerance hypothesis
◦ 1957 – Clonal selection theory (Frank Macfarlane Burnet)
◦ 1957 – Discovery of interferon by Alick Isaacs and Jean Lindenmann
◦ 1958–1962 – Discovery of human leukocyte antigens (Jean Dausset and others)
◦ 1959–1962 – Discovery of antibody structure (independently elucidated by Gerald Edelman and
Rodney Porter)
◦ 1959 – Discovery of lymphocyte circulation (James Gowans)
◦ 1960 – Discovery of lymphocyte "blastogenic transformation" and proliferation in response to mitogenic lectins-
phytohemagglutinin (PHA) (Peter Nowell)
◦ 1961–1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)
◦ 1960 – Radioimmunoassay – (Rosalyn Sussman Yalow)
◦ 1961 – Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell)
◦ 1963 – Development of the plaque assay for the enumeration of antibody-forming cells in vitro by Niels Jerne and
Albert Nordin
◦ 1963 – Gell and Coombs classification of hypersensitivity
◦ 1964–1968 – T and B cell cooperation in immune response
◦ 1965 – Discovery of lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein) (J.
Gordon) and (L.D. MacLean)
◦ 1965 – Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock)
◦ 1965 – Secretory immunoglobulins
◦ 1967 – Identification of IgE as the reaginic antibody (Kimishige Ishizaka)
◦ 1968 – Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and
Ronald D. Guttmann)
◦ 1969 – The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini)
◦ 1971 – Peter Perlmann and Eva Engvall at Stockholm University invented ELISA
◦ 1972 – Structure of the antibody molecule
◦ 1973 – Dendritic Cells first described by Ralph M. Steinman
◦ 1974 – Immune Network Hypothesis (Niels Jerne)
◦ 1974 – T-cell restriction to MHC (Rolf Zinkernagel and (Peter C. Doherty)
◦ 1975 – Generation of monoclonal antibodies (Georges Köhler) and (César Milstein)[4]
◦ 1975 – Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein, Hans Wigzell)
◦ 1976 – Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa)
◦ 1980–1983 – Discovery and characterization of interleukins, 1 and 2 IL-1 IL-2 (Robert Gallo, Kendall A. Smith,
Tadatsugu Taniguchi)
◦ 1983 – Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler)[5]
(James Allison)
◦ 1983 – Discovery of HIV (Luc Montagnier) (Françoise Barré-Sinoussi) (Robert Gallo)
◦ 1985–1987 – Identification of genes for the T cell receptor
◦ 1986 – Hepatitis B vaccine produced by genetic engineering
◦ 1986 – Th1 vs Th2 model of T helper cell function (Timothy Mosmann)
◦ 1988 – Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E.
Rudd)
◦ 1990 – Gene therapy for SCID
◦ 1991 – Role of peptide for MHC Class II structure
◦ 1992 – Discovery of transitional B cells (David Allman & Michael Cancro)
◦ 1994 – 'Danger' model of immunological tolerance (Polly Matzinger)
◦ 1995 – James P. Allison describes the function of CTLA-4
◦ 1995 – Regulatory T cells (Shimon Sakaguchi)
◦ 1995 – First Dendritic cell vaccine trial reported by Mukherji et al.
◦ 1996 – 1998 – Identification of Toll-like receptors
◦ 1997 – Discovery of the autoimmune regulator and the AIRE (autimmune regulator) gene.
◦ 2000 – Characterization of M1 and M2 macrophage subsets by Charles Mills
◦ 2001 – Discovery of FOXP3 – the gene directing regulatory T cell development
◦ 2005 – Development of human papillomavirus vaccine (Ian Frazer)
◦ 2006 – Antigen-specific NK cell memory first reported by Ulrich von Andrian's group after discovery by
Mahmoud Goodarzi
◦ 2010 – The first autologous cell-based cancer vaccine, PROVENGE, is approved by the FDA for the
treatment of metastatic, asymptomatic stage IV prostate cancer. The treatment is marketed at a cost of
$93,000 and imparts, on average, only an extra four months of life expectancy. The manufacturer,
Dendreon Inc, declares bankruptcy in 2014.
◦ 2010 – First immune checkpoint inhibitor, ipilimumab (anti-CTLA-4), is approved by the FDA for
treatment of stage IV melanoma
◦ 2011 – Carl H. June reports first successful use of CAR T-cells expressing the 4-1BB costimulatory
signaling domain for the treatment of CD19+ malignancies
◦ 2014 – A second class of immune checkpoint inhibitor (anti-PD-1) is approved by the FDA for the
treatment of melanoma. Two different drugs, pembrolizumab and nivolumab are approved within
months of each other.
◦ 2016 – Halpert and Konduri first characterize the role of dendritic cell CTLA-4 in Th immune
polarization
◦ 2016 – A third class of immune checkpoint inhibitor, anti-PD-L1 (atezolizumab), is approved for the
treatment of bladder cancer
◦ 2017 – The first autologous CAR T-cell therapy tisagenlecleucel also known as Kymriah is approved for
the treatment of pediatric B-ALL. Marketed at a cost of $475,000, the treatment provides an 83% rate of
durable remission among poor prognosis patients for whom a bad outcome would otherwise be
expected. A second autologous CAR T-cell therapy axicabtagene ciloleucel (Yescarta) is approved
months later.
◦ 2020 - The first modified mRNA vaccine is developed for the prevention of SARS-CoV-2 infection. This
breakthrough technology allowed design, testing, and potential approvalof a prophylactic vaccine in
under one year.
◦ 2020- Phase 3 of the clinical trial of the COVID vaccine from Pfizer was found to have 90% efficacy.
VII. ASSIGNMENT
VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM) Quiz
1 (Chapter 1)
1. This division of Immunology involves the use of immune system components to treat a disease or
disorder (1 point)
a. Reproductive immunology c. Clinical immunology
b. Immunotherapy d. Classical immunology
2. Give the name of 4 scientist/s and his/her discovery/contribution to the field of immunology (4 points)
IX. REFERENCES
College: COLLEGE OF VETERINARY MEDICINE
Campus : Bayombong Campus
Chapter 2
This chapter will introduce the basic concepts on the phenomenon of immunity with emphasis on
the different mechanisms employed by the body to protect against infection.
At the end of this chapter, the students will be able to able to understand the general concepts of immune
response of the body towards antigens.
VIII. V. LESSON CONTENT
Acquired immunity
- is a complex and sophisticated system that provides the ultimate defense of the body
- acquired immune system recognize and destroy foreign invaders and retain the memory of the encounter
- Has 2 categories- the humoral immune response and the cell mediated immune response
IX. Antibody
- also called immunoglobulin, a protective protein produced by the immune system in response to the presence of a
foreign substance, called an antigen. Antibodies recognize and latch onto antigens in order to remove them from the
body.
X. VII. ASSIGNMENT
VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM) Quiz 2
(Chapter 2)
1. Give 2 examples of body’s defenses? (2 points)
2. Differentiate primary from secondary immune response. (4 points)
3. True or False. Memory cells come from T-lymphocytes (1 point)
4. Explain how antibodies are produced (3 points)
Chapter 2b
Antigens
• An antigen is a substance/molecule that, when introduced into the body, triggers the production of an antibody
by the immune system.
• The term is derived from the generation of antibodies to such substances.
• Often antigens are foreign proteins (or parts of them) that enter the body via an infection.
• Sometimes, however, the body's own proteins, expressed in an inappropriate manner (where or when they
are not usually seen), are treated like antigens by the immune system.
• It is important to recognize that bacteria or viruses are not themselves antigens but they contain antigens both
on their surface and inside them.
• Some components are better able to stimulate the immune response than others.
• These components are said to be more “antigenic”.
Types of antigens
MICROBIAL ANTIGENS
Bacterial antigens
Viral antigens
Other microbial antigens
NON-MICROBIAL ANTIGENS
Cell surface antigens
autoantigens
BACTERIAL ANTIGENS
- Bacteria are either ovoid or spherical
- Cytoplasm is surrounded by a cell membrane
- Other bacterial antigens are porins (proteins that form pores on surface of Gram-negative bacteria; heat shock
proteins (produced when bacteria is stressed), and exotoxins
- Exotoxins are immunogenic and stimulate production of antibodies known as “antitoxins”
- Exotoxins that are modified to lose toxicity by retain immunogenicity are called “toxoids” (ex. Tetanus toxoid from
Clostridium tetani ). Viral antigens
- Viruses are small obligate intracellular parasites that consist of a nucleic acid core surrounded by a layer of protein
subunits.
- Protein layer is called capsid and the subunits are called capsomeres
- Capsid proteins are good antigens
- Viruses incorporate their nucleic acid in the cell’s genome and start producing new proteins which are then displayed
on the surface of the cell
- Viral proteins that are synthesized are called “endogenous antigens”
- Antigens that come from the outside are called “exogenous antigens” Other microbial antigens
Fungi
Protozoan parasites
Parasitic worms
- Consists of proteins, carbohydrates, lipids, and nucleic acids
- Nonmicrobial antigens
- Food may contain foreign molecules that may trigger an immune response
- Dust may contain pollens grains or fungal spores
- Mosquito or snake bites can introduce foreign molecules (saliva and venom) - Organ grafts
- Cell-surface antigens
- Proteins that are found on cell surfaces
- These can cause an immune response when injected into another species of animal
- Blood-group antigens are antigens found on the surface of RBCs
- MHCs (Major Histocompatibility Complex) molecules are group of molecules which trigger Graft rejection
autoantigens
- An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by
the immune system of patients suffering from a specific autoimmune disease
- These antigens should, under normal conditions, not be the target of the immune system, but, due to mainly genetic
and environmental factors, the normal immunological tolerance for such an antigen has been lost in these patients
Chapter 2c
Immune Tolerance
TOLERANCE
Some Definitions
2. primed (= "experienced")
Both T cells and B cells that have encountered the antigen for which they are specific. If they receive a second,
costimulatory signal, they become
Having received a second signal from an antigen-presenting cell, they become metabolically more active and begin
rounds of mitosis (= clonal expansion).
If activated, "professional" APCs can always provide the second signal for T cells. Dendritic cells are professional
APCs, and sometimes macrophages may be.
Nonprofessional APCs can present antigen but not the second signal. B cells are nonprofessional — they present
antigen to T-helper cells, but these must already be activated by an earlier encounter with professionals.
5. effector cells. o B cells that have differentiated into antibody-secreting plasma cells.
o T cells that have differentiated into
CD8+ cytotoxic T lymphocytes (CTL)
CD4+ T cells (Th1) that release cytokines producing a cell-mediated immune response
CD4+ Th2 helper cells which promote the synthesis of IgE by B cells.
Tfh cells which also stimulate B cells to develop into antibody-secreting plasma cells.
Th17 cells which promote inflammation.
6. memory cells.
Experienced T (or B) cells that have returned to — or remained in — a quiescent state.
Immunological tolerance is the process by which the immune system does not attack an antigen
Can be natural/self-tolerance or induced
3 forms
-central
-peripheral
-acquired
Natural tolerance -The body does not mount an immune response to self antigens
Induced tolerance -Tolerance to external antigens can be created by manipulating the immune system
Central Tolerance
- Occurs during lymphocyte development and operates in the thymus and bone marrow
- T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent
cells, preventing autoimmunity
- This process is most active in fetal life, but continues throughout life as immature lymphocytes are generated
- In mammals the process occurs in the thymus (T cells) and bone marrow (B
cells), when maturing lymphocytes are exposed to self antigens.
Positive selection occurs first when naive T-cells are exposed to antigens in the thymus.
T-cells which have receptors with sufficient affinity for self-MHC molecules are selected. Other cells that do
not show sufficient affinity to self-antigens will undergo a deletion process known as death by neglect which
involves apoptosis of the cells. The positive selection is a classical example of the importance of some
degree of autorreactiveness. This does not occur in B-cells.
Negative selection of T-cells with a very high affinity of self-MHC molecules are induced to anergy, or
lineage divergence to form T-regulatory cells.
Peripheral Tolerance
Immunological tolerance developed after T and B cells mature and enter the “periphery”
Occurs in the secondary lymphoid organs or the peripheral circulation.
Acquired Tolerance
Acquired or induced tolerance refers to the immune system's adaptation to external antigens characterized
by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would
likely induce cell-mediated or humoral immunity
One of the most important natural kinds of acquired tolerance is immune tolerance in pregnancy , where the
fetus and the placenta must be tolerated by the maternal immune system.
In adults, tolerance may be induced by repeated administration of very large doses of antigen, or of small
doses that are below the threshold required for stimulation of an immune response
Another example of acquired tolerance is during organ transplant. Immuno-suppression and a variety of
medicine are used to produce acquired tolerance and to prevent rejection.
VII. ASSIGNMENT
VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM)
Rahman MS, Rahman MK, Saha S, Kaykobad M, Rahman MS. Antigenic: An improved prediction model of
protective antigens. Artif Intell Med. 2019 Mar;94:28-41. doi: 10.1016/j.artmed.2018.12.010. Epub 2019 Jan 3.
PMID: 30871681.
An Immunology lecture prepared by V. A
l
Antibodies, also called “immunoglobulins”, are
one of two important protein molecules of the
immune system that engage in the recognition
of pathogens or other foreign material
It is produced by B-lymphocytes (soluble
form)
It is also found on the surfaces of B
lymphocytes and called B cell receptors
(BCR)
Immunoglobulin’s function is the recognition of
a specific antigen
based on chemical and structural differences
are classified in five distinct classes of
molecules called isotypes that are named IgM,
IgG, IgA, IgD, and IgE.
Chapter 5
Subsets of T- lymphocytes
This chapter will discuss the different populations of T-lymphocytes and their functions, activation, and interactions with other cells.
At the end of this chapter, the students will be able to distinguish the different types of Tlymphocytes and their associated function. The
student will also be able to explain how lymphocytes perform their functions and illustrate the mechanisms involved in activating them in the
presence of different pathogens/antigens.
V. LESSON CONTENT
XX. Introduction
• The T cell repertoire in a healthy adult is shaped by thymic selection (positive and negative), where naive CD4+ and CD8+ T cells can then
interact, and be primed, with “foreign” antigen in the secondary lymphoid tissues
• Antigen engagement via the T cell receptor (TCR) then shapes the repertoire of antigen-specific T cells and most likely the functional attributes
of the T cell
• Multiple phenotypes of both CD4+ and CD8+ T cells have been identified which have differing functions
• The key to understanding T cell immunity is knowing the types of T cells and how they expand and contract with antigen and how this process
is regulated
• In this section, we will deal with Treg cells and how immunity to microbes is regulated and suppressed
• The cells of the adaptive immune system, in contrast to those of the innate immune system, interact with the environmental agent in a highly
discriminative way, i.e., they display specificity, heterogeneity, and memory.
• These functions are primarily carried out by two types of cells that are involved in the recognition of antigen:
o (1) the thymus-dependent or T lymphocytes, which participate in cellular responses against intracellular pathogens, organ
transplants, and malignant cells
o (2) the bone marrow or bursal-dependent B lymphocytes, which provide humoral immunity, i.e., antibody-mediated immunity
against extracellular pathogens, their toxins, and other environmental substances.
• As outlined in the previous section, a third group of cells involved in the presentation of antigen to T cells, i.e., APCs, include dendritic cells,
macrophages, and B cells (Table 1-8).
• APCs take up predominantly protein antigens, cut them into pepti-des, bind the peptides to major histocompatibility complex (MHC) molecules,
and display these presented antigens on their cell surface, where they can be recognized and bound by antigen receptors on T lymphocytes.
• T lymphocytes are identified by a surface cluster of differentiation (CD) molecule named CD3 and are comprised of two major groups: the CD4
and CD8 populations
• The CD4 cells display helper activities on other populations of cells, and in turn are subdivided into at least Th1, Th2, Th9, Th17 and T regulatory
(Treg) groups, each with a characteristic profile of production cytokines.
• The CD8 T cytotoxic population is the second major group of T lymphocytes that function in killing target cells; they are comprised of Tc1 and
Tc2 subpopulations with similar cytokine profiles as Th1 and Th2 cells.
• Collectively, the T lymphocytes play or facilitate a central role in the orchestration of all functions of the adaptive immune system and perform
four important tasks:
o (1) promotion of inflammation by cytokine production (Th1 and Th17 cells) o (2) helping B lymphocytes (Th2 cells) o
(3) regulating immunosuppressive responses (T regulatory cells) o (4) killing of unwanted target
cells (CTL)
XXII. Antigen Processing and Presentation Follows Different Pathways for Cytosolic (Endogenous) and Vesicular
(Exogenous) Antigen
• T lymphocytes play a pivotal role in both cell-mediated and humoral immune responses of the adaptive immune system.
• These functions are carried out by T lymphocytes that interact with antigen through the TCR.
• The processing of antigen can occur at two sites: (1) at the level of APCs or (2) at the target cell site.
• Phagocytes and other APCs play major roles in internalizing, processing, and presentation of ‘‘processed antigen’’ to T lymphocytes for induction
of immune responses carried out by both CD4 and CD8 lymphocyte populations.
• Antigen can also be processed and presented to T lymphocytes at the target cell site in a cell that has been infected with a virus, for example,
or modified by a chemical or by malignant transformation.
• Shown in Figure 1 is a schematic representation of the two modes of antigen processing at these two sites that determines which MHC the
processed antigen will react with.
Figure 1. Schematic representation of the two modes of antigen processing. Panel A: Shows the endogenous pathway, which presents processed
antigen (i.e., peptides) from a target cell to a CD8þ lymphocyte in the context of MHC-I. Panel B: Shows the exogenous pathway, which presents the
peptide products from an APC to a CD4+ lymphocyte in the context of MHC-II. [Reproduced with permission from Bellanti, JA (Ed). Immunology IV:
Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].
• In the case of antigens processed by APCs by the exogenous pathway, CD4 T cells recognize antigen that has been processed into peptide
fragments (epitopes) that are then placed in a groove of the MHC-II molecule, and presented to the TCR on subsets of helper T cells (called CD4+
cells).
• Other antigens found within cells, e.g., target cells, are processed through an endogenous pathway and are delivered by MHC-I to TCR of
‘‘cytotoxic’’ T cells (CD8+ cells).
XXIII. The Interaction Between APC and T Cells Influences Which T Cells Are Activated
• CD4+ T cell activation results in the secretion of cytokines that help and regulate other cells (see Chapter 9, Bellanti, JA (Ed). Immunology
IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012).
• The pattern of cytokine expression defines the subsets of CD4+ T cells: Th1, Th2, Treg1, Th3, and Th17 cells.
• Th1 cells secrete interferon gamma (IFN-y) and create a milieu in which key cytotoxic effectors— macrophages, natural killer cells, and cytotoxic
CD8+ T lymphocytes—are activated, generating cellmediated immunity.
• Th2 cells secrete IL-4 and IL-10 (and other cytokines) and help antigen-primed B lymphocytes differentiate into plasma cells and secrete
antibodies, the effector molecules of humoral responses.
• T cells, Treg cells, with the phenotype CD4+CD25+, express the signature transcription factor FOXP3 and usually secrete IL-10 and transforming
growth factor beta (TGF-B).
• Cells with this phenotype are thought to recognize self-antigens and function to prevent autoimmunity and are also involved in chronic viral
infections, allergy, transplantation, and malignancy.
• Th17 cells represent a wide variety of recently described cells involved in inflammation through the elaboration of proinflammatory cytokines
and interact with IL-23 (see Chapter 9, Bellanti, JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press,
Bethesda, MD, 2012).
• As described in the previous section, T cells can recognize peptide fragments that have been processed and presented by APC, i.e., dendritic
cells (DC), macrophages, and B cells.
• Figure 1-21 depicts the shaping of T cell subsets after interacting with antigen and the polarization of T cells in response to different cytokines
• Production of Th1, Th2, Th17, and two populations of Treg cells Th3 and TR1 (Figure 2), which have a variety of interactions with other cells in
performing the following functions:
o promotion of inflammation by cytokine production (Th1 lymphocytes); o helping B lymphocytes (Th2
lymphocytes); o regulating immunosuppressive responses (Treg lymphocytes).
Figure 2. Panel A: The two main T cell populations are CD4+ and CD8+ cells. The CD4 are helper T cells and are shown highlighted with the CD4+
subsets Th1, Th17, Th2, Th3, and Tr1 and shown below are the CD8 cytotoxic T cells (faded). Panel B: Shows the molecular events in the immunologic
synapse at the CD4+/dendritic cell interface together with the cytokines that induce the Th0 differentiation into each of the subsets.
[Reproduced with permission from Bellanti, JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].
• The Th population has several effector subsets (Figure 1), including Th1, Th2, Th17, and Treg, which have roles in delayed hypersensitivity,
antibody production, inflammation, and immunosuppression (or regulation), respectively
• Th are the key orchestrators of adaptive immunity in mammals, and each effector subset mobilises a distinct module of antimicrobial immunity:
o Th direct elimination of intracellular microbial pathogens and tumors o Th2 induce expulsion of helminths o Th17 promotes resistance to
extracellular bacteria and fungi, playing important roles in protection at mucosal surfaces and in promotion of autoimmune inflammation,
as well as participating in antitumor immune responses
o Treg suppress inflammatory reactions and ensure host autoreactive lymphocytes do not mount a response against host tissues or
innocuous environmental antigens o CTL have Tc1 and Tc2 subsets: Tc1 destroy virally-infected or malignant cells (Figure 3)
Figure 3. Schematic representation of the two major pathways of T cell differentiation: the Th and Tc populations and their subsets. Following uptake
and processing of an antigen by an APC shown in the figure as a dendritic cell, peptide is presented either to the CD8 population in the context of
MHC-I or to the CD4 subpopulation in the context of MHC-II following which a cascading set of cellular lymphoproliferative and differentiative steps
are initiated under the inductive influence of cytokines that ultimately determine their effector functions [Reproduced with permission from Bellanti
JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].
XXV. T cell Classification
T-cell type T-cell Glycopro Antigenpresenting Foreign Function or
receptor tein molecule stimulus defining
type corecept characteristics
or
Naive Any Any Any Any Has not
encountered an
antigen
Th1 αβ CD4 MHC II Virus/intracell Activates
ular bacteria macrophages;
causes other
cells to go on
guard against
a virus,
quarantining
it
Th2 αβ CD4 MHC II Parasites Stimulates
eosinophils,
basophils, and
mast cells to
eliminate
parasite;
stimulates B cells
to produce IgE
and IgA
antibodies
Th9 αβ CD4 MHC II Parasites Supports CD4 +
T-cell expansion
and survival;
recruits mast
cells
Th17 αβ CD4 MHC II Extracellular Recruits
bacteria/fungi neutrophils,
which kill many
bacteria and
fungi
T-follicular αβ CD4 MHC II Any In follicles of
helper (Tfh) spleen and
tonsils,
stimulates
Bcell
production
of
highaffinity
antibodies
Regulatory αβ CD4 MHC II NA Regulates T-cell
T cell (Treg) activation and
proliferation
Cytotoxic T αβ CD8 MHC I Any Releases vesicles
lymphocyte containing
(CTL) perforin, which
punctures the
target cell, and
granzyme, which
induces
apoptosis,
into the vicinity
of infected cells,
destroying them
XXVII. Th1 Cells Signal Macrophages to Kill Engulfed Intracellular Bacterial Pathogens
• Mycobacterium tuberculosis is an example of a bacterium that can be phagocytosed by macrophages and is able to protect itself from being
killed by virtue of its intracellular location within the phagolysosome.
• The organism can now replicate in the phagosome, protected from the harmful effects of the humoral antibody immune response.
• Th1 cells recognize peptides on the macrophage membrane in association with MHC-II, produce cytokines, and signal the macrophage with IFN-
g together with other cytokines to kill the bacteria.
• Other Th1 cytokines also attract more macrophages to the infection site and activate them to produce inflammatory cytokines that result in
delayed-type hypersensitivity, e.g., the TST.
• One outcome of the host-microbial interaction between the macrophage and the intracellular location of the tubercle bacillus is the killing of
the tubercle bacillus resulting from enhanced macrophage killing of the bacillus by activation by IL-12 and later Th1 production of IFN-g
• Or there is failure of killing when the replication of the tubercle bacillus overwhelms the macrophage capacity.
XXVIII. Activated CD8 Cytotoxic T Lymphocytes kill target cells
• Cytotoxic CD8+ T cells effect their function by recognizing peptide bound to MHC-I
• The peptide has been endogenously processed either directly (derived from viral genes, such as HIV) or indirectly, through cross-presentation
(derived from effete or dead bacterially infected cells, such as mTB).
• Figure 4 shows activated CD8+ cytotoxic T lymphocytes recognizing a bacterial peptide presented by HLA-B27 (derived from Immunopaedia
case study: 14 year old with severe hip pain)
• This causes liberation of cytotoxic granules (perforin and granzymes) from the CD8+ T cell which then cause lysis and apoptosis of infected target
cells
Figure 4. Recognition of a bacterial peptide by activated CD8+ cytotoxic T lymphocytes after crosspresentation and endogenous processing of the
bacterial proteins. Killing is effected by the release of granzymes and perforin from the activated CD8 cell upon contact. [from Immunopaedia case
study: 14 year old with severe hip pain].
Cell-mediated
immunity
VMIC 4 lecture
Topic
XXIX. Duality of Immune System
Antibody production
T-Dependent antigens:
• Antibody production requires assistance from T helper (TH ) cells.
• A macrophage cells ingest antigen and presents it to TH cell. • TH cell
stimulates B cells specific for antigen to become plasma cells.
• Antigens are mainly proteins on viruses, bacteria, foreign red blood cells,
and hapten-carrier molecules.
T-Independent Antigens:
• Antibody production does not require assistance from T cells.
• Antigens are mainly polysaccharides or lipopolysaccharides with
repeating subunits (bacterial capsules).
• Weaker immune response than for T-dependent antigens.
XXX. Cell Mediated Immune Responses
Primary function of cell mediated response
• Eliminate intracellular pathogens
• Eliminate tumor cells
Both Ag-specific and non-specific cells are involved
• Ag-specific: CD8+ cells (TC) and TH (DTH)
• Non-specific: Macrophages (MΦ), neutrophils, NK cells
Both Ag-specific and non-specific cells require cytokines
• Induction of CMI
• Depends on Nature of Antigenic stimulus
• Best developed after following infection with
intracellular parasites
• Live vaccines highly stimulating • Killed vaccine not
very effective
• But effective if it contains Freund type adjuvant.
Functions of T-cells
• Cytotoxic T-cells
recognize antigen on
surface of
virusinfected cells,
tumor cells, allograft
cells with MHC1 and
sectored lymphokines and destroy
target cells
Functions of T-cells
Functions of T-
cells
MHC II molecule – leads to
release of Biological
Mediators Lymphokines – activate
Macrophages and kills
intracellular parasites
cells