Immunology-Abbas Jorge Salinas

Activation of T Lymphocytes
OVERVIEW OF CELL-MEDIATED IMMUNITY
Effector CD4+ T cells are generated by antigen recognition in secondary lymphoid organs but most
of them leave these organs and migrate to peripheral sites of infection where they function in
microbe elimination
migration is largely independent of antigen,
VLA-4 and VLA-5 (do limfocito), bind to fibronectin in extracellular matrices, and a third adhesion
molecule, CD44, which is also highly expressed on activated T cells
As a result, antigen-specifc effector and memory T cells that encounter the antigen are
preferentially retained at the extravascular site.
T cells not specific for the antigen that migrate into a site of inammation may die in the tissue or
return through lymphatic vessels to the circulation.
T cells greatly enhance this function of phagocytes
T cells recognize microbial protein antigens and recruit and
activate phagocytes
CD4+ effector T cells activate phagocytes via:
CD40 ligand, and secreted cytokines.
T celldependent injurious reaction is called
delayed-type hypersensitivity (DTH), the term
hypersensitivity referring to tissue damage caused by an immune
response.
SUBSETS OF CD4+ EFFECTOR T CELLS
TH1, TH2, and TH17
follicular helper T cells, is important for antibody responses.
Regulatory T cells are another distinct population of CD4+ T cells.
They are not effector cells;
Properties of TH1, TH2, and TH17 Subsets
The immune reaction to intracellular bacteria like
Mycobacterium tuberculosis is dominated by activated
macrophages
characteristics of differentiated are the cytokines they
produce, thetranscription factors they express, and epigenetic
changes in specific cytokine gene loci.
IFN- for TH1, IL-4, IL-5, and IL-13 for TH2 cells; and IL-17 and
IL-22 for TH17
TH1: express high levels of the chemokine
receptors CXCR3 and CCR5, bind to chemokines during innate
immune responses. TH1 is abundant at sites of infection where
the infectious agents trigger strong innate
immune reactions; bacteria and viruses. also express high levels of ligands for E-selectin and P-
selectin (migration of these cells to sites of strong inammation)
 TH2: receptors CCR3, CCR4, and CCR8 recognize chemokines at sites of helminthic infection or Jorge Salinas
allergic reactions, particularly in mucosal tissues.
TH17: express CCR6, which binds the chemokine CCL20, by various tissue cells and macrophages in
some bacterial and fungal infections
In many inammatory reactions T cells that produce both IFN- (TH1) and IL-17 (TH17).
Conversely, some cells may produce cytokines that are not characteristic ( IL-9) led to an expanding
nomenclature describing these populations (such as TH9, TH22, and so on)

T cells are considered the source of many cytokines in protective and pathologic adaptive immune
responses. Cytokines may be produced by other cell types, such as T cells and innate lymphoid
cells.
Development of TH1, TH2, and TH17 Subsets
differentiation involves transcriptional activation and epigenetic modifcation of cytokine genes.
1- Induction: Cytokines induce the transcription of cytokine genes
2- Commitment: Continued activation may that the genes that encode cytokines not produced
by that subset to remain inactive.
3- Amplifcation: accumulation of cells of one subset
The cytokines that drive the development of CD4+ T cell subsets are produced by APCs (dendritic
cells and macrophages) and other immune cells (such as NK cells and basophils or mast cells)
Different microbes may stimulate dendritic cells to produce distinct sets of cytokines
NK cells and mast cells, also produce cytokines that inuence the pattern of T cell subset
development
Stimuli other: dendritic cells selectively promote either TH1 or TH2 differentiation; may be true for
TH17 cells
The transcription factors are themselves activated or induced by signals from antigen receptors,
innate immune receptors, costimulators, and other cytokine receptors epigenetic changes in
cytokine gene loci correlate with stable phenotypes.
effector cells produces cytokines that promote its own developmentprovides a powerful
amplification mechanism.
IFN- secreted by TH1 cells promotes further TH1 differentiation and inhibits the generation of
TH2 and TH17 cells. Similarly, IL-4 (TH2) and IL-21 (TH17)
An immune response develops along one effector pathway. Most extreme polarization is seen in
chronic infections or in chronic exposure to environmental antigens
Differentiation is best able to combat:
development of TH1 cells is driven by intracellular microbes,
to helminthic parasites by the development of TH2 cells
TH17 responses are induced by some bacteria and fungi
THE TH1 SUBSET Jorge Salinas

induced by microbes that are ingested by and activate phagocytes, and is the major effector T
cell population
Development of TH1 Cells
is driven mainly by the cytokines IL-12 and IFN- in response to microbes
that activate dendritic cells, macrophages, and NK cells
many intracellular bacteria, such as Listeria and mycobacteria, and by
parasites, such as Leishmania,
also stimulated by viruses and by protein antigens with strong adjuvants.
A common feature of these infections and immunization conditions is the
production of certain cytokines, including IL-12, IL-18, and type I
interferons.
All of these cytokines promote TH1 development; of these, IL-12 is
probably the most potent
NK cells produce IFN- a strong TH1-inducing cytokine, also acts on
dendritic cells and macrophages to induce more IL-12 secretion.
T cells enhance cytokine production by dendritic cells and macrophages,
by virtue of CD40 ligand (CD40L) on activated T cells engaging CD40 on
the APCs and stimulating IL-12 secretion
IFN- and IL-12 activate the transcription factors T-bet, STAT1, and
STAT4
T-bet induced in response to antigen and IFN-, promote the
production of INF- . (positive amplification loop)
STAT1 Induced by IFN-, stimulates expression of T-bet.
STAT4 induced in response to IL-12, enhances IFN- production.
Functions of TH1 Cells
The principal function of TH1 cells is to activate macrophages to ingest and destroy microbes.
involved in injurious delayed-type hypersensitivity,
Typical of tuberculosis and is also seen in some other infectious and inammatory disorders
Also stimulate the production of some IgG antibodies.
Interferon-
(immune or type II interferon)
The principal macrophage-activating cytokine and serves critical functions in immunity against
intracellular microbes
It is not a potent antiviral cytokine, but its a potent activator of effector cells of the immune
system classical macrophage activation (CMA)
Produced by CD4+ TH1 cells, NK cells and CD8+ T and NK cells, in response to activating ligands on
the surface of infected or stressed host cells or in response to IL-12.
IFN- functions as a mediator of innate immunity
 Enhanced by IL-12 and IL-18 Jorge Salinas

CMA in innate responses: IFN- is produced by NK acts on macrophages together with Toll-like
receptor (TLR) signals delivered by microbes
In adaptive: works together with CD40 ligand
IFN- acts on B cells to promote switching to certain IgG subclasses, and to inhibit switching to IL-
4dependent isotypes, such as IgE
IgG bind to Fc receptors on phagocytes (promote the phagocytosis of opsonized microbes) and
activate complement
The major source of IFN- in antibody responses follicular helper T and not classical TH1 cells
stimulates expression of several different proteins that contribute to enhanced MHC-associated
antigen presentation and the initiation and amplification of T celldependent immune responses
(TAP) and components of the proteasome; HLA-DM; and B7 costimulators on APCs.
Other TH1 Cytokines
TNFcontribute to the recruitment of leukocytes and enhanced inammation
IL-10 This is an example of a negative feedback loop in T cell responses.
TH 1-Mediated Classical Macrophage Activation and Killing of Phagocytosed Microbes
(NA PERIFERIACD4 que j foi ativado no linfondo)
by CD40L-CD40 interactions and by IFN-together they are
potent stimuli for macrophage activation.
CD40 signals activate B (NF-B) and AP-1 stimulate the
expression of several enzymes in the phagolysosomes
These toxic substances may also be released into adjacent tissues,
where they kill extracellular microbes and may cause damage to
normal tissues
interactions between the surface molecules ensures that macrophages
that are presenting antigens are also the macrophages that will be in
contact with T cells and thus most efficiently activated by the T cells.

mutations in CD40L (X-linked hyper-IgM syndrome)highly

susceptible to infections
Activated macrophages secrete (TNF, IL-1, and chemokines, and
short-lived lipid mediators such as prostaglandins, leukotrienes,
and platelet-activating factor)
They recruit more leukocytes
The microbicidal products released by activated macrophages and neutrophils are capable of
injuring normal tissue and do not discriminate between microbes and host tissue.
THE TH2 SUBSET Jorge Salinas

Is the mediator of phagocyte-independent defense, in which eosinophils and mast cells play
central roles or the eradication of helminthic infections and perhaps also for elimination of other
microbes in mucosal tissues.
Development of TH2 Cells
by the cytokine, IL-4 in response to helminths and allergens
in response to microbes and antigens that cause persistent or
repeated T cell stimulation without much inammation If the
antigen also does not trigger inammation with attendant IL-12 the
localconcentration of IL-4 gradually increases increasing
differentiation of TH2.
where does the IL-4 come from before TH2 cells develop?==> IL-4 is
produced by mast cells and, possibly, other cell populations, such as
innate lymphoid cells
STAT6 Induced by IL-4
GATA-3 Induced by IL-4 together with TCR signals. enhancing
expression of the TH2 cytokine genes IL-4, IL-5, and IL-13 (in the same
genetic locus)similar way where T-bet inuences IFN- expression
*GATA-3 blocks TH1 by inhibiting expression of the signaling chain of
the IL-12 receptor
Functions of TH2 Cells
TH2 cells stimulate IgE- mast cell- and eosinophil to eradicate
helminthic infections
Interleukin-4
inducer and an effector cytokine of these cells (TH2)
Produce by: TH2 and activated mast cells.
IL-4 stimulates B cell Ig heavy chain class switching to the IgE isotype.
IgEprincipal mediator of immediate hypersensitivity (allergic)
reactions, and production of IL-4 is important for the development
of allergies (block IgGsantagonist of INF-gamma)
IL-13 can also contribute to switching to the IgE isotype
cells that stimulate isotype switching may be TFH cells (that
produce IL-4 and IL-13) and not classical TH2 cells.
IL-4 and IL-13 suppress IFN-mediated classical macrophage
activation inhibit defense against intracellular microbes
IL-4 (and IL-13) stimulate peristalsis and IL-13 increases mucus
secretion
IL-4 and IL-13 stimulate eosinophils, promoting the expression of
adhesion molecules
 Interleukin-13 Jorge Salinas

IL-13 is structurally and functionally similar to IL-4

Produce by: basophils, eosinophils, and NKT cells
Cells that are stimulated: B cells, mononuclear phagocytes, dendritic cells, eosinophils, basophils,
fibroblasts, endothelial cells, and bronchial epithelial cells.
T cells do not express the IL-13 receptor
induce alternative macrophage activation contributes to tissue repair and fibrosis.
Interleukin-5
an activator of eosinophils and by activated mast cells.
stimulate the growth and differentiation of eosinophils
Roles of TH2 Cells in Host Defense
Activates the eosinophils to release their granule
contents (by IL-5)
Activation of mast cells by coating the cells with IgE
(Fce receptors) and may be activated by antigens
The granule contents: include vasoactive amines and TNF
Host defense at mucosal barriers.
IL-4 and IL-13 activate macrophages to express enzymes
that promote collagen synthesis and fbrosis. Collagen
synthesis (IL-13, transforming growth factor- [TGF-]),
and new blood vessel formation or angiogenesis
IL-4 inhibit TH1 development and function by the
stimulation of IL-10 and TGF- by alternatively activated
macrophages.

THE TH17 SUBSET

primarily involved in recruiting leukocytes and inducing inammation, are critical for destroying
extracellular bacteria and fungi, and also contribute signifcantly to inammatory diseases.
Development of TH17 Cells
stimulated by proinammatory cytokines produced in response to bacteria and fungithey act on
dendritic cells and stimulate the production of cytokines including IL-6, IL-1, and IL-23, all of which
promote TH-17
Whereas IL-6 and IL-1 stimulate the early steps in TH17 differentiated, IL-23 is more important for
the proliferation and maintenance
TGF-promotes the development of proinammatory TH17 cells when IL-6 or IL-1, are present
transcription factors RORt and STAT3
TGF-, IL-6 IL-1production of RORt (the retinoic acid receptor family)
IL-6activate the transcription factor STAT3
 TH17 cells appear to be abundant in mucosal tissues by providing high local concentrations of Jorge Salinas
TGF- and innate inammatory cytokines
important in combating intestinal infections and in the development of intestinal inammation
Clostridium species are particularly potent inducers of TH17 cells
Functions of TH17 Cells
combat microbes by recruiting leukocytes, mainly neutrophils
neutrophils are a major defense mechanism against extracellular bacteria and fungi
Interleukin-17
link between T cellmediated adaptive immunity and the acute inammatory response
Induces neutrophil-rich inammation. stimulates the production of TNF that recruit neutrophils
and, monocytes to the site. Also enhances neutrophil generation (G-CSF)
Other TH17 Cytokines
IL-22 that its produce by some NK cells and group 3 innate lymphoid cells
Produced in epithelial tissues, especially of the skin and gastrointestinal tractpromoting the
barrier function of epithelia, inducing production of anti-microbial peptides also contributes to
inammationstimulating epithelial production of chemokines
IL-21 and follicular helper T cells. and follicular helper T cells. effects on B and T cells and NK cells.
important function of IL-21 is in antibody responses, especially the reactions that occur in germinal
centers is
required for the generation of follicular helper T cells and
stimulates B cells in germinal centers. s also promote the differentiation of TH17 cells autocrine
amplifying IL-21 increasing the proliferation, differentiation, and effector function of CD8+ T cells
and
NK cells
Roles of TH17 Cells in Host Defense
destroy
extracellular bacteria and fungi, mainly by inducing neutrophilic inammation
Jobs syndrome mutations in STAT3 increased susceptibility to cutaneous fungal and bacterial
infections
TH1 and TH17 cells function cooperatively in phagocyte-mediated elimination of microbes in cell-
mediated
immunity
TH17 cells are
probably the most important effector T cells for recruiting phagocytes
, they may be activated by TH1 cells
to ingest and destroy the microbes
TH17 cells contribute to the pathogenesis of many inammatory diseases.
Associated with psoriasis, inammatory bowel disease, rheumatoid arthritis, and multiple sclerosis.
Agents that block the TH17 cells for several of these diseases, and have shown impressive effcacy in
psoriasis
 the role of TH17 cells in these diseases is uncertain. TH1 and TH17 cells may both be present in Jorge Salinas
the lesions in various inammatory diseases,
FUNCTIONS OF OTHER T CELL SUBSETS
T cells and NKT cells
recognize a wide variety of antigens, many of which are not peptides, and these are not displayed
by class I and class II MHC
have limited diversity, but are abundant in epithelial tissues, such as the gastrointestinal tract
special roles in host defense, similar to the roles of innate lymphoid cells common functions:
Early defense against microbes encountered at epithelia
Surveillance against stressed cells
Production of cytokines that inuence later adaptive immune responses
T Cells
The antigen receptor of MHC composed of heterodimers of and chains associates with the CD3
and proteins, in the same way as TCR
contain different V regions in their antigen receptors, reside in different tissues, and
have a limited capacity to recirculate among these tissues
limited diversity of the TCRs
do not recognize MHC-associated peptide antigens and are not MHC restricted recognizesmall
phosphorylated molecules, alkyl amines, or lipids in mycobacteria and other microbesrecognize
protein or non-protein antigens that do not require processing or any particular type of APCs are
triggered by microbial heat shock proteins
NKT Cells
A small population markers by CD56; The TCR have limited diversity characterized by a V region
these cells are also called invariant NKT (iNKT) cells.
recognize lipids that are bound to class I MHClike molecules called CD1
NKT cells and lipid antigenspecifc T cells are rapidly producing IL-4 and IFN-help marginal
zone B cells to produce antibodies against lipid antigens.
mediate protective innate immune responses against some pathogens, such as mycobacteria
regulate adaptive immune responses primarily by secreting cytokines