2. INTRODUCTION
The development of an effective immune response involves
lymphoid cells, inflammatory cells, and hematopoietic cells.
The complex interactions among these cells are mediated by a
group of proteins collectively designated cytokines to denote
their role in cell-to-cell communication.
2
3. Introduction
Cytokines are low molecular weight regulatory proteins or
glycoproteins
secreted by white blood cells and various other cells in the body in
response to a number of stimuli.
These proteins assist in regulating the development of immune
effector cells
And some cytokines possess direct effector functions of their own.
3
4. Introduction
Many referred as interleukins
Secreted by leukocytes and act
on other leukocytes
IL-1 through IL 29 have been
described
4
5. Chemokines
Group of low molecular
weight cytokines
Affect chemotaxis and
other aspects of
leukocyte behaviour
Play important role in
inflammatory response
5
6. PROPERTIES
1. Bind to specific receptors on the membrane of target cell
2. Cytokine receptors may be made up from several different
chains
3. Cytokines & their fully assembled receptors exhibit very
high affinity for each other & deliver intracellular signals
4. Particular cytokine bind to receptors on the membrane
i. Autocrine action
ii. Paracrine action
iii. Endocrine action
6
9. PROPERTIES
5. Cytokines regulate the intensity & duration of immune
response
6. Binding of a given cytokine to responsive target cells
generally stimulates increased expression of cytokine
receptors and secretion of other cytokines
7. Exhibit attributes of pleiotropy, redundancy, synergy,
antagonism and cascade induction
8. Share many properties with hormones
9
12. Cytokines belong to four families
• Falls in 4 families
i. Hematopoietin family
ii. Interferon family
iii. Interleukin family
iv. Tumor necrosis factor family
• All have molecular mass less than 30kDa
• All have similarities and few rarely act alone
12
13. Cytokines belong to four families
• The amino acid sequences of these family members differ
considerably
• All have high degree of α helical structure and little or no β
sheet structure
• Molecules have similar polypeptide fold, with for α helical
regions (A-D)
• In which the 1st and 2nd helices & the 3rd and 4th helices run
roughly parallel to one another & are connected by loops
13
16. Cytokines have numerous
biological functions
• Although a variety of cells can secrete cytokines, the principal
producers are Tн cells, dendritic cells, and macrophages
• Cytokines released from these cell types activate an entire
network of interacting cells
16
17. Cytokines have numerous
biological functions
• Among numerous physiological responses that require
cytokine involvement are
Development of cellular and humoral immune responses
Induction of inflammatory response
Regulation of hematopoiesis
Control of cellular proliferation
Differentiation
Healing of wounds
17
18. Cytokines have numerous
biological functions
What keeps cytokines fromactivating cells in a non specific
fashion during the immune response?
18
19. Cytokines have numerous
biological functions
What keeps cytokines fromactivating cells in a non specific
fashion during the immune response?
Specificity is maintained by careful regulation of the
expression of cytokine receptors on cells
Cytokine receptors are expressed on a cell only after that cell
has interacted with antigen, limiting cytokine response to
antigen activated lymphocytes
19
20. Cytokines have numerous
biological functions
Specificity maintained if cytokine secretion occurs only when
the cytokine-producing cell interacts directly with target cell,
thus ensuring that effective concentrations of the cytokine
occur in the vicinity of the intended target.
In case of Tн cell, a major producer of cytokines, cellular
interactions occurs when the T-cell receptor recognizes an
antigen-MHC complex on an appropriate antigen-presenting
cell, such as a macrophage, dendritic cell, or B lymphocyte.
20
21. Cytokines have numerous
biological functions
• The concentration of cytokines secreted at the junction of
these interacting cells reaches high enough local
concentration to affect the target APC, but not more distant
cells.
• Half-life of cytokines in the blood stream or other
extracellular fluids into which they are secreted is usually very
short, ensuring that they act for only a limited period and
thus over a short distance.
21
23. Cytokine Receptors
• Cytokine receptors fall into 5 families
Immunoglobulin superfamily receptors
Class I cytokine receptor family (also known as hematopoietin
receptor family)
Class II cytokine receptor family (also known as interferon receptor
family)
TNF receptor family
Chemokine receptor family
23
29. Cytokine receptors initiate
signaling
• Although some cytokine receptors lie outside the class I and
class II families, majority are included within these two
families.
• Class I and class II cytokine receptors lack signaling motifs
• Unifying model emerged from studies of the molecular events
triggered by binding of IFN-γ to its receptor, a member of the
Class II family
29
30. Interferon gamma
• Originally discovered because of its ability to induce cells to
block or inhibit the replication of a wide variety of viruses
• Antiviral activity is a property it shares with IFN-α and IFN-β
• IFN-γ plays a central role in many immunoregulatory
proteins including
i. Regulation of mononuclear phagocytes
ii. B cell switching to certain IgG classes
iii. Support or inhibition of the development of Tн cell subsets
30
31. Cytokine receptors initiate
signaling
• The cytokine receptor is composed of separate subunits
• Different inactive protein kinases are associated with different
subunits of the receptor.
• Cytokine binding induces the association of the two separate
cytokine receptors subunits and activation of the receptor-
associated JAKs.
31
32. Cytokine receptors initiate
signaling
• Activated JAKs create docking sites for the STAT transcription
factors by phosphorylation of specific tyrosine residues on
cytokine receptor subunits.
• After undergoing JAK-mediated phosphorylation, STAT
transcription factors translocate from receptor docking sites
at the membrane to the nucleus, where they initiate the
transcription of specific genes.
32
34. Cytokine receptors initiate
signaling
• In addition to IFN-γ, a number of other class I and class II
ligands have been shown to cause dimerization of their
receptors.
• An important element of cytokine specificity derives from the
exquisite specificity of the match between cytokine and their
receptors.
• Another aspect of cytokine specificity is that each particular
cytokine induces transcription of a specific subset of genes in
a given cell type; the resulting gene products then mediate the
various effects typical of that cytokine.
34
35. Cytokine receptors initiate
signaling
• Specificity is traceable to three factors
i. Particular cytokine receptors start particular JAK-STAT
pathways
ii. Transcriptional activity of activated STATs is specific
because a particular STAT homodimer/heterodimer will
only recognize certain sequence motifs & thus can interact
only with the promoters of certain genes.
iii. Only those target genes whose expression is permitted by a
particular cell type can be activated within that variety of
cell
35
36. Cytokine receptors initiate
signaling
• i.e., in any given cell type only subset of the potential target
genes of a particular STAT may be permitted expression.
• For eg., IL-4 induces one set of genes in T cells, another in B
cells and third in eosinophils.
• IL-1 does not signal via the JAK-STAT pathway but utilizes a
kinase designated IL-1 receptor-associated kinase, or IRAK.
• IRAK proteins also utilized by TLRs for signal transduction
36
37. Cytokine antagonists
Number of proteins can inhibit cytokine activity
○ Can bind to receptor, fail to activate the cell, OR
○ Can bind directly to cytokine, inhibiting it
Enzymatic cleavage of receptors and release of these can bind cytokines in the blood
- Marker of chronic T cell activation (transplant rejection, AIDS)
Viruses have developed strategies
○ Cytokine homologs
○ Soluble cytokine binding proteins
○ Homologs of cytokine receptors
○ Interference with intracellular signaling
○ Interference with cytokine secretion
○ Induction of cytokine inhibitors in the host cell
37
38. Cytokine antagonists
• Epstein-Barr virus (EBV) produces an IL-10-like molecule that
binds to the IL-10 receptor and like cellular IL-10, suppresses
Tн 1-type cell-mediated responses which are effective against
many intracellular parasites such as viruses.
• Molecules produced by viruses that mimic cytokines allow the
virus to manipulate the immune response in ways that aid the
survival of the pathogen.
38
39. Cytokine antagonists
EBV also produce an inducer of IL-1 Ra, the host antagonist of
IL-1.
The pox viruses have been shown to encode a soluble TNF-
binding protein and a soluble IL-1 binding protein.
Since both TNF and IL-1 exhibit a broad spectrum of activities
in the inflammatory response, these soluble cytokine-binding
proteins may prohibit or diminish the inflammatory effects of
the cytokines, thereby conferring on the virus a selective
advantage.
39
41. Cytokine secretion by Tн1 and
Tн2 subsets
• CD4⁺ TH cells exert most of helper functions through secreted
cytokines, which either act on the cells that produce them in an
autocrine fashion or modulate the responses of other cells
through paracrine pathways.
• Although CD8⁺ CTLs also secrete cytokines, their array of
cytokines generally is more restricted than that of CD4⁺ Tн cells.
• Two CD4⁺ Tн cell subpopulations designated Tн1 and Tн2 can be
distinguished in vitro by the cytokines they secrete.
• Both subsets secrete IL-3 and GM-CSF but differ in the other
cytokines they produce.
41
42. Cytokine secretion by Tн1 and
Tн2 subsets
TH1 and Tн2 cells are characterized by the following functional differences:
• TH1 subset is responsible for many cell-mediated functions, such as delayed-
type hypersensitivity & activation of TC cells, & for the production of
opsonization-promoting IgG antibodies, that is, Ab that bind to the high-
affinity Fc receptors of phagocytes and interact with the complement system.
– Associated with promotion of excessive inflammation & tissue injury.
• TH2 subset stimulates eosinophil activation, and differentiation, provides help
to B cells, promotes production of large amounts of IgM, IgE, and non-
complement activating IgG isotypes
• Supports allergic reactions
42
43. Cytokine secretion by Tн1 and
Tн2 subsets
• Differences in the cytokine secreted by Tн1 and Tн2 cells
determine the different biological functions of these subsets.
• A defining cytokine of the Tн1 subset, INF-γ, activates
macrophages, stimulating these cells to increase microbicidal
activity, up-regulate the level of class II MHC, secrete
cytokines such as IL-12, which induces Tн cells to differentiate
into the Tн1 subset.
• IFN-γ secretion by Tн1 cells also induces antibody class
switching to IgG classes that support phagocytosis and
fixation of complement. 43
44. Cytokine secretion by Tн1 and
Tн2 subsets
• TNF-β and IFN-γ are cytokines that mediate inflammation, and
it is their secretion that accounts for the association of Tн1 cells
with inflammatory phenomena such as delayed
hypersensitivity.
• Tн1 cells produce IL-2 and IFN-γ cytokines that promote the
differentiation of fully cytotoxic Tс cells from CD8+ precursors.
• This pattern of cytokine production makes the Tн1 subset
particularly suited to respond to viral infections and
intracellular pathogens.
• Finally, IFN-γ inhibits the expansion of the Tн2 population.
44
45. Development of Tн1 and Tн2
subsets determination
• The cytokine environment in which antigen-primed Tн cells
differentiate determines the subset that develops.
• IL-4 is essential for the development of a Tн2 response, and IFN-γ,
IL-12, and IL-18 all are important in the physiology of the
development of Tн1 cells.
• Tн1 development is also critically dependent on IFN-γ, which
induces a number of changes, including the up-regulation of IL-12
production by macrophages and dendritic cells, and the
activation of the IL-12 receptor on activated T cells, which it
accomplishes by up-regulating expression of the chain of the
IL-12 receptor.
45
46. Development of Tн1 and Tн2
subsets determination
• IL-18, promotes proliferation and IFN-γ production by both
developing and fully differentiated Tн1 cells and by NK cells.
• So a regulatory network of cytokines positively controls the
generation of Tн1 cells.
46
48. Development of Tн1 and Tн2
subsets determination
• The generation of Tн2 cells depends critically on IL-4.
• Exposing naive helper cells to IL-4 at the beginning of an
immune response causes them to differentiate into Tн2 cells.
• This influence of IL-4 is predominant in directing Tн cells to
the Tн2 route.
48
49. Cytokine profiles are cross
regulated
• The critical cytokines produced by Tн1 and Tн2 subsets have two
characteristic effects on subset development.
1. promote the growth of the subset that produces them
2. inhibit the development and activity of the opposite subset, an
effect known as cross-regulation
• IFN- γ (secreted by the Tн1 subset) preferentially inhibits
proliferation of the Tн2 subset, and IL-4 and IL-10 (secreted by the
Tн2 subset) down-regulate secretion of IL-12, one of the critical
cytokines for Tн1 differentiation, by both macrophages and
dendritic cells.
49
50. Cytokine profiles are cross
regulated
• Cross regulation- when antibody production is high, cell-
mediated immunity is low, and vice versa.
• Two transcription factors, T-Bet and GATA-3, are key elements in
determining subset commitment and cross-regulation.
• The expression of T-Bet drives cells to differentiate into Tн1 cells
and suppresses their differentiation along the Tн2 pathway.
• Expression of GATA-3 does the opposite, promoting the
development of naive T cells into Tн2 cells while suppressing their
differentiation into Tн cells.
50
52. TH1/TH2 balance determines
disease outcomes
• The progression of some diseases may depend on the balance
between the Tн1 and Tн2 subsets.
• In humans, a well-studied example of this phenomenon is leprosy,
which is caused by Mycobacterium leprae, an intracellular
pathogen that can survive within the phagosomes of
macrophages.
• In tuberculoid leprosy, a cell-mediated immune response forms
granulomas, resulting in the destruction of most of the
mycobacteria, so that only a few organisms remain in the tissues.
• Although skin and peripheral nerves are damaged, tuberculoid
leprosy progresses slowly and patients usually survive.
52
53. TH1/TH2 balance determines
disease outcomes
• In lepromatous leprosy, the cell-mediatedresponse is
depressed and, instead, humoral antibodies are formed,
sometimes resulting in hypergammaglobulinemia.
• The mycobacteria are widely disseminated in macrophages,
often reaching numbers as high as 1010 per gram of tissue.
• Lepromatous leprosy progresses into disseminated infection
of the bone and cartilage with extensive nerve damage.
53
54. Cytokine Related Diseases
Defects in the complex regulatory networks governing the
expression of cytokines and cytokine receptors have been
implicated in a number of diseases.
Genetic defects in cytokines, their receptors, or the molecules
involved in signal transduction following receptor-cytokine
interaction lead to immunodeficiencies such as severe
combined immunodeficiency (SCID).
Other defects in the cytokine network can cause inability to
defend against specific families of pathogens.
54
55. Cytokine Related Diseases
• For eg., people with a defective receptor for INF-γ are
susceptible to mycobacterial infections that rarely occur in the
normal population.
• In addition to the diseases rooted in the genetic defects in
cytokine activity, a number of disease conditions result from
overexpression or underexpression of the cytokine or cytokine
receptors.
• Therapies aimed at preventing the potential harm caused by
cytokine activity
55
56. 1. Septic shock
• Bacterial infections remain a major cause of septic shock,
which may develop a few hours after infection by certain
Gram negative bacteria including E.coli, Klebsiella
pneumoniae, Pseudomonas aeruginosa, Enterobacter
aerogenes, and Neisseria meningitidis.
• Symptom- drop of blood pressure, fever, diarrhea and wide
spread clotting of blood in various organs.
56
57. Septic shock
• Bacterial septic shock apparently develops because bacterial
cell wall endotoxins bind TLRs on dendritic cellls and
macrophages, causing them to overproduce IL-1 and TNF-α to
levels that cause septic shock.
• A common feature of sepsis is an overwhelming production of
proinflammatory cytokines such as TNF-α and IL-1β.
• The cytokine imbalance often causes very abnormal body
temperature and respiratory rate and high white blood cell
counts, followed by capillary leakage, tissue injury, and lethal
organ failure
57
58. Septic shock
• The increases in TNF-α and IL-1 occur rapidly in early sepsis,
so neutralizing these cytokines is most beneficial early in the
process.
• Appr. 24 hrs following onset of sepsis, the levels of TNF-α and
IL-1 fall dramatically, and other factors become more
important.
• Cytokines critical in the later stages may include IL-6, MIF,
and IL-8.
58
59. 2. Bacterial toxic shock is caused
by superantigens
• A variety of MO produce toxins that act as superantigens.
• Superantigens bind simultaneously to class II MHC molecule
and to the variable domain Vβ domain of the T-cell receptor,
activating a particular Vβ domain.
• Because of their unique binding ability, superantigens can
activate large numbers of T cells irrespective of their antigenic
specificity.
59
60. Bacterial toxic shock is caused by
superantigens
• Bacterial superantigens have been implicated as the causative
agent of several diseases, such as bacterial toxic shock and food
poisoning.
• Included among these bacterial superantigens are several
enterotoxins, exfoliating toxins, and toxic shock syndrome toxin
(TSST) from S aureus and Mycoplasma arthritidis supernatant
(MAS).
• The large no of T cells activated by these superantigens results in
excessive production of cytokines.
• TSST, for eg, shown to induce extremely high levels of TNF-α & IL-1
60
61. 3.Lymphoid and myeloid cancers
• Abnormalities in the production of cytokines or their
receptors have been associated with some types of cancer.
• For eg, abnormally high levels of IL-6 are secreted by cardiac
myxoma cells, myeloma and plastocystoma cells, and cervical
and bladder cancer cells.
• In myeloma & plastocytoma cells, IL-6 appears to operate in
an autocrine manner to stimulate cell proliferation.
• When Mabs to IL-6 are added to invitro cultures of myeloma
cells, their growth is inhibited.
61
62. 4. Chaga’s disease
• Causative agent- Trypanosoma cruzi, characterised by severe
immune suppression
• Evidence that soluble factor produced by T. cruzi leads to
reduction in T cell IL-2 (CD25) receptor
62
63. Cytokine-based Therapies
• Problems with cytokine therapies:
o Effective dose levels
o Short half-life
o Potent biological response modifiers
• Can cause unpredictable side effects
63
65. Cytokines in hematopoiesis
• Many cytokines have been shown to play essential roles in
hematopoiesis.
• During hematopoiesis, cytokines act as developmental signals
that direct commitment of progenitor cells into and through
particular lineages.
• Suitable concentrations of a group of cytokines including IL-3,
GM-CSF, IL-1 and IL-6 will cause it to enter differentiation
pathways that lead to the generation of monocytes,
neutrophils and other leukocytes of the myeloid group
65
66. Cytokines in hematopoiesis
• The participation f leukocytes in immune response often
results in their death and removal.
• Hematopoetic cytokines that stimulate production of
neutrophils (G-CSF), myleoid cells (GM-CSF), platelets (IL-11),
and RBCs (erythropoietin) have been used in clinical
applications, most often as supportive therapy for patients
with immunodeficiency resulting from a genetic defect or
from cancer chemotherapy.
66
72. Monokines
• A monokine is a type of cytokine produced primarily
by monocytes and macrophages.
• Examples include interleukin 1 and tumor necrosis factor-
alpha.
• Other monokines include alpha and beta interferon,
and colony stimulating factors.
72
73. Interleukeins
• They are secreted regulatory proteins produced
by lymphocytes, monocytes and various other cell types and are
released by cells in response to antigenic and non-antigenic stimuli.
Consist of IL1 to IL37.
• IL-1 activates Antigen Presenting Cells and CD4+ lymphocytes; affects
the differentiation of the B-Cells and T-Cells and other
immunocompetent cells and takes part in the regulation of production
of other cytokines and GM-CSF (Granulocyte-Macrophage Colony-
Stimulating Factor).
73
74. Interleukeins
• IL-2 stimulates the proliferation and activation of B-Cells and T-
Cells. IL-4 plays a role in the differentiation of TH2, in allergic
responses, and in the switching of antibody types.
• IL-3 is a potent activator of hemopoietic cells. It stimulates NK-Cells
and acts as a synergist with IL-4 during the induction of CD4+
lymphocyte activation process.
• IL-5 stimulates the production and maturation of eosinophils during
inflammation.
• IL-7 is known as the growth factor of the immature B-Cells and T-
Cells. It induces apoptosis of tumor cells and causes differentiation
of cells from a subgroup of acute myeloblastic leukemia.
74
75. Interleukeins
• IL-8 acts as a chemotactic factor that attracts neutrophils,
basophils and T-Cells to sites of inflammation.
• IL-9 stimulates the excretion of IL-2, IL-4, IL-6, IL-11, and
takes part in a stimulation of cytotoxicity of T-killers and NK-
Cells, inducing apoptosis.
• IL-10 acts to repress secretion of pro-inflammatory cytokines.
• IL-11 is a pro-inflammative factor, which regulates the
functions of B-Cells and T-Cells. It also takes part in the
induction of various killer cells activities and acts as an
autocrine factor for the proliferation of megacaryocytes.
75
76. Interleukeins
• IL-12 is a critical linker between the innate immunity and adaptive
immunity, capable of TH1 (T Helper Type-1) differentiation and IFN-
Gamma release by T-Cells and NK cells.
• IL-13 is very sensitive to monocytes and B-Cells. IL-13 does not act on T-
Cells but inhibits the proliferation of leukemic pro-B-Cells.
• IL-14 is a BCGF (B-Cell Growth Factor) and the hyper production of
this interleukin enables the progression of NHL-B (B-cell Type Non
Hodgkin's lymphoma).
• IL-15 is analogous to IL-2 and increases the anti-tumor activities of T-
killers and NK-Cells, and the production of cytokines CD4+
lymphocytes.
76
77. Interleukeins
• IL-17 is principally produced by CD4+ T-Cells, which induces
granulopoiesis via GMCSF. It takes part in the regulation of
many cytokines and can reinforce the antibody dependant
tumor cell destruction.
• IL-18 acts as a synergist with IL-12, especially in the induction
of IFN-Gamma production and inhibition of angiogenesis.
• IL-19 is produced mainly by monocytes and is similar to IL-10
in its function. It is stimulated by GM-CSF and regulates the
functions of macrophages, and also suppresses the activities
of TH1 and TH2.
77
78. Interleukeins
• IL-21 executes an important role in the regulation of
hematopoiesis and immune response. It promotes a high
production of T-Cells, fast growth and maturation of NK-
Cells and B-Cells population.
• IL-22 is produced by activated T-Cells in acute inflammation.
It is similar to IL-10 in function, but does not prohibit the
production of pro-inflammatory cytokines through
monocytes.
78
79. Interferons
• Based on the type of receptor through which they signal, human interferons
have been classified into three major types.
1. Interferon type I:
All type I IFNs bind to a specific cell surface receptor complex known
as the IFN α receptor (IFNAR) that consists
of IFNAR1 and IFNAR2 chains. The type I interferons present in
humans are IFN-α, IFN-β and IFN-ω.
2. Interferon type II:
Binds to IFNGR that consists of IFNGR1 and IFNGR2 chains. In
humans this is IFN-γ.
3. Interferon type III:
Signal through a receptor complex consisting of IL10R2 (also called
CRF2-4) and IFNLR1 (also called CRF2-12). 79
80. Chemokines
• Chemokines have been classified into four main subfamilies :
1. CXC Chemokines (contain CXL1 to CXL17)
2. CC Chemokines (contain CCL1 to CCL28)
3. CX3C Chemokines (contain CX3CL1)
4. XC Chemokines (contain XCL1 & XCL2)
• All of these proteins exert their biological effects by interacting with G
protein-linked transmembrane receptors called chemokine receptors,
that are selectively found on the surfaces of their target cells.
80
81. Colony stimulating factors
• Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to
receptor proteins on the surfaces of hemotopoietic stem cells, thereby
activating intracellular signaling pathways that can cause the cells
to proliferate and differentiate into a specific kind of blood cell.
• The colony-stimulating factors are soluble, in contrast to other,
membrane-bound substances of the hematopoietic microenvironment.
• They transduce by paracrine, endocrine, or autocrine signaling.
• Colony-stimulating factors include:
– CSF1 - Macrophage colony-stimulating factor(MCSF)
– CSF2 - Granulocyte macrophage colony stimulating factors(GMCSF).
– CSF3 - Granulocyte colony-stimulating factors(GCSF)
81
82. Tumor necrosis factors
• Tumor necrosis factors (or the TNF family) refer to a group of cytokines that
can cause cell death (apoptosis).
• Nineteen cytokines have been identified as part of the TNF family on the
basis of sequence, functional, and structural similarities. They include:
• Tumor necrosis factor (TNF), formerly known as TNFα or TNF alpha, is the
best-known member of this class. TNF is a monocyte-derived cytotoxin that
has been implicated in tumor regression, septic shock, and cachexia.
• Lymphotoxin-alpha, formerly known as Tumor necrosis factor-beta (TNF-
β), is a cytokine that is inhibited by interleukin 10.
• Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two
related cytokines produced by lymphocytes that are cytotoxic for a wide
range of tumor cells in vitro and in vivo.
82
83. Tumor necrosis factors
• T cell antigen gp39 (CD40L), a cytokine that seems to be
important in B-cell development and activation.
• CD27L, a cytokine that plays a role in T-cell activation. It induces
the proliferation of co-stimulated T cells and enhances the
generation of cytolytic T cells.
• CD30L, a cytokine that induces proliferation of T cells.
• FASL, a cytokine involved in cell death.
• 4-1BBL, an inducible T cell surface molecule that contributes to T-
cell stimulation.
• OX40L, a cytokine that co-stimulates T cell proliferation and
cytokine production.
• TNF-related apoptosis inducing ligand (TRAIL), a cytokine that
induces apoptosis. 83