T - helper cells’ cytokine

profiles

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Immunology

MSc 1 biotechnology

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T cells

• T cells are those specialized cells of the immune system which mature in

the thymus.

• Mature T cells are stored in secondary lymphoid organs (lymph nodes,

spleen, tonsils, appendix, and Peyer’s patches in the small intestine). These

cells circulate in the bloodstream and the lymphatic system. After they first

encounter an infected or abnormal cell, they are activated and search for

those particular cells.

• Killer (cytotoxic) T cells attach to antigens on infected or abnormal (for

example, cancerous) cells. Killer T cells then kill these cells by making

holes in their cell membrane and injecting enzymes into the cells.

• Suppressor (regulatory) T cells produce substances that help end the

immune response or sometimes prevent certain harmful responses from

occurring.

• For this presentation, let us concern ourselves with the third type- Helper T

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Helper T cells

• Helper T cells help other immune cells. Some helper T cells help B cells

produce antibodies against foreign antigens. Others help activate killer T

cells to kill infected or abnormal cells or help activate macrophages,

enabling them to ingest infected or abnormal cells more efficiently.

• They help the activity of other immune cells by releasing T cell cytokines.

• Some helper T cells help B cells produce antibodies against foreign

antigens. Others help activate killer T cells to kill infected or abnormal cells

or help activate macrophages, enabling them to ingest infected or abnormal

cells more efficiently.

• Their importance in the immune system can be seen by observing HIV

infections, which target the mature T helper cells (which express the CD4

protein and are termed CD4 T cells)

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Cytokines

• Cytokines are a large class of proteins playing vital roles in cell signalling.

• They are released by cells to manipulate the behaviour of others, and in some cases, manipulate the releasing cell itself.

• Cytokines include chemokines, interferons, interleukins, lymphokines, tumour necrosis factors but not hormones or growth factors.

• They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations.

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Path followed during an immune

response

• Recognition

• Verification

• Proliferation

• Maturation

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Recognition (Signal 1)

• (APCs) endocytose foreign material (typically bacteria or viruses), which undergoes processing, then travel from the infection site to the lymph nodes.

• Once at the lymph nodes, the APC begin to present antigen peptides that are bound to Class II MHC, allowing CD4+ T cells that express the specific T cell Receptors against the peptide/MHC complex to activate.

• When a TH cell encounters and recognises the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule.

• These interactions bring these proteins closer together, allowing the intracellular kinases present on the TCR, CD3 and CD4 proteins to activate each other via phosphorylation.

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Verification (Signal 2)

• This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen.

• If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming anergic (anergy is generated from the unprotected biochemical changes of Signal 1). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate throughout the body with no value until they undergo apoptosis.

• The second signal involves an interaction between CD28 on the CD4+ T cell and the proteins CD80 (B7.1) or CD86 (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as co-stimulatory molecules. The second signal is considered obsolete since signal 1 does the activation.

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Proliferation

• Once the two-signal activation is complete the

T helper cell (TH) then allows itself to

proliferate. It achieves this by releasing a

potent T cell growth factor called interleukin 2

(IL-2) which acts upon itself in an autocrine

fashion.

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Maturation

• After many cell generations, the TH cell's progenitors differentiate into effector TH cells, memory TH cells, and regulatory TH cells.

• A Effector TH cells secrete cytokines, proteins or peptides that stimulate or interact with other leukocytes, including TH cells.

• B Memory TH cells retain the antigen affinity of the originally activated T cell, and are used to act as later effector cells during a second immune response (e.g. if there is re-infection of the host at a later stage).

• C Regulatory T cells do not promote immune function, but act to decrease it instead. Despite their low numbers during an infection, these cells are believed to play an important role in the self-limitation of the immune system; they have been shown to prevent the development of various auto-immune diseases.

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Subtypes

• Proliferating helper T cells that develop into effector T cells

differentiate into two major subtypes of cells known as TH1

and TH2 cells

• These subtypes are defined on the basis of the specific

cytokines they produce i.e. TH1 and TH2 produce various

types of interleukins to provoke various bespoke responses

• Exception: interleukin-12 (IL-12) plays an essential role

during TH1 development, however IL-12 is not produced by

helper T cells themselves, but by certain professional APCs,

such as activated macrophages and dendritic cells.

• Future Prospects include studying proliferation, stabilization

and epigenetic remodelling of th1 and th2 cytokines

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Subtypes

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Cytokine Profile

• Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they

produce and respond to and the immune responses they are involved in. Th1 cells produce pro-

inflammatory cytokines like IFN-gamma, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-

5, IL-6 and IL-13. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of

microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies directed

toward large extracellular parasites (see “IL-4 signalling Pathway”). IL-5 stimulates eosinophil responses,

also part of the immune response toward large extracellular parasites (see “IL-5 signalling Pathway”)

• Th1 and Th2 are produced by differentiation from a non-antigen exposed precursor cell type, THP.

Exposure of THP cells to antigen by antigen-presenting cells may result in their differentiation to Th0 cells,

not yet committed to become either Th1 or Th2 cells, although the existence of Th0 cells is controversial.

Cells committed as either Th1 and Th2 cells are called polarized, whether they are effector cells actively

secreting cytokines or are memory cells. The stimulation of THP cells by exposure to antigen-presenting

cells induces the proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The

differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 causes Th1

differentiation and blocks Th2 cell production (see “IL12 and Stat4 Dependent signalling Pathway in Th1

Development” pathway), while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18

also induces Th1 differentiation (See “IL-18 signalling pathway”). Polarized Th1 and Th2 cells also express

distinct sets of chemokine receptors that further modify their homing and other cellular responses (see

“Selective expression of chemokine receptors during T-cell polarization” pathway). Improved

understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune

system, its response to infection and aberrant responses that lead to disease.

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Cytokine Profile

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Models of Helper T cells

TH 1 Model

• TH1 cells produce interferon-

gamma (IFN-gamma) and

tumour necrosis factor-beta

(TNF-beta, also known as

lymphotoxin).

• Cytokines in the TH1 response

maximise the killing efficiency

of the macrophages and the

proliferation of cytotoxic

CD8+ T cells.

TH 2 Model

• TH2 cells produce interleukin-

4 (IL-4), interleukin-5 (IL-5)

and interleukin-13 (IL-13),

among numerous other

cytokines.

• Cytokines of the TH2 system

stimulate B-cells into

proliferation, to undergo

antibody class switching, and

to increase antibody

production.

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Models of Helper T cells

TH 1 Model

• The Type 1 cytokine IFN-gamma increases production ofinterleukin-12 by dendriticcells and macrophages, and bypositive feedback of IL-12stimulating IFN-gammaproduction, promotes the TH1cytokine profile.

• IFN-gamma also inhibits theproduction of interleukin-4, animportant cytokine associatedthe Type 2 response, and thusit acts to preserve its ownresponse.

TH 2 Model

• The Type 2 pathway increasesthe production of IL-4 onhelper T cells and alsoexpresses IL-10 which inhibitsIL-2 and IFN-gamma

• It promotes both theproduction of its owncytokines while inhibiting theestablishment of the TH1response, ensuring that oncethe T cell has made thatchoice, it stays that way

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TH 1 Model

• Produces a cytokine profilethat causes inflammation andactivates certain T cells andmacrophages.

• Delayed hypersensitivity

• TC cell activation

• Production of opsonization-promoting IgG Abs (i.e., Absthat bind to the high affinityFcRs of phagocytes andinteract with complement, suchas IgG2a in mice)

TH 2 Model

• Activates mainly B cells andimmune responses that dependupon Ab.

• Stimulates eosinophilactivation and differentiation

• Provides help to B cells

• Promotes the production ofrelatively large amounts ofIgM, IgE, and noncomplement-activating IgGisotypes

• Supports allergic reactions

Models of Helper T cells

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References

• Daniel Mucida, Hilde Cheroutre; The Many

Facelifts of CD4 Helper Cells; Advances in

Immunology, Volume 107, Chapter 5

• Albert’s Molecular Biology Of The Cell;

Chapter 25: The Adaptive Immune System:

Effector Helper T Cells Help Activate Other

Cells of the Innate and Adaptive Immune

Systems

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