15.4H: T Helper cells

T cells are T lymphocytes that belong to the CD4⁺ subset. These cells have a number of direct functions, but they get their name from the help they provide to other types of effector cells, such as B cells and cytotoxic T lymphocytes (CTLs). The help consists of secreted cytokines that stimulate the helped cells.

Types of Helper T Cells

Four kinds have been identified:

• Th1
  • These participate in both cell-mediated immunity and antibody-mediated immunity. They are essential for controlling such intracellular pathogens as viruses and certain bacteria, e.g., Listeria and Mycobacterium tuberculosis (the bacillus that causes TB). They provide cytokine-mediated "help" to cytotoxic T lymphocytes — perhaps the body's most potent weapon against intracellular pathogens.
• Th2
  • These provide help for B cells and are essential for the production of IgE antibodies and assist in the production of some subclasses of IgG as well. Antibodies are needed to control extracellular pathogens (which unlike intracellular parasites are exposed to antibodies in blood and other body fluids).
• Tfh
  • These also provide help to B cells enabling them to develop into antibody-secreting plasma cells. This occurs in nests of lymphoid cells called follicles — in the lymph nodes. The most abundant helper T cells there are B-cell helpers called follicular helper T (Tfh) cells.
• Th17
  • These protect surfaces (e.g., skin, lining of the intestine) against extracellular bacteria.

In addition, there is another related subset that dampens rather than promotes immune responses. These cells, designated Treg, are discussed on another page. Link to it.

Origin of Helper T Cells

Like all T cells, Th cells arise in the thymus.

• When they acquire CD4, they are called pre-Th cells.
• When they are presented with both an antigen and appropriate cytokines,they begin to proliferate and become activated.
• It is the nature of the stimulation — the type of antigen-presenting cell and cytokine(s) — that determines which path they enter.

Th1 Cells

Figure 15.4.8.1 Th1 and Th2 cells

Th1 cells are produced when dendritic cells and pre-Th cells form an immunological synapse in which the dendritic cell presents antigen to the T cell's receptor for antigen (TCR), and secretes interleukin 12 (IL-12) as well as IFN-γ. The paracrine stimulation by these cytokines causes the Th1 cells to secrete their own lymphokines:

• interferon-gamma (IFN-γ)
• tumor-necrosis factor-beta (TNF-β) (also known as lymphotoxin)

These stimulate macrophages to kill the bacteria they have engulfed, recruit other leukocytes to the site producing inflammation, act on B cells to promote antibody class switching, and help cytotoxic T cells (CTL) do their work and probably help convert some of them to memory cells.

Th2 Cells

Th2 cells are produced when antigen-presenting cells (APCs) present antigen (e.g., on parasitic helminth worms or certain allergens) to the T cell's receptor for antigen (TCR) along with

• the costimulatory molecule B7 (CD80 & 86)
• the paracrine stimulants interleukin 4 (IL-4) and interleukin 2 (IL-2).

The identity of the APCs for Th2 responses is still uncertain. Some research indicates that basophils are the APCs, but other research questions this role.

The major lymphokines secreted by Th2 cells are

• interleukin 4 (IL-4). This
  • stimulates class-switching in B cells and promotes their synthesis of IgE antibodies.
  • acts as a positive-feedback device promoting more pre-Th cells to enter the Th2 pathway.
  • blocks the IFN-γ receptors from entering the immunological synapse on pre-Th cells thus inhibiting them from entering the Th1 path (shown in red).
• Interleukin 13 (IL-13). This also promotes the synthesis of IgE antibodies as well as recruiting and activating basophils.
• Interleukin 5 (IL-5). Attracts and activates eosinophils.

Two transcription factors have been found that play a critical role in the choice between becoming a Th1 or a Th2 cell.

• T-bet for Th1 cells
• GATA3 for Th2 cells

T-bet produces Th1 cells by

• turning on the genes needed for Th1 function (e.g., for IFN-γ)
• blocking the activity of GATA3.

Mice whose genes for T-bet have been "knocked-out" lack Th1 cells and have elevated numbers of Th2 cells (making them susceptible to such Th2-mediated disorders as asthma).

GATA3 produces Th2 cells by

• turning on the genes needed for Th2 function (e.g., for IL-5)
• blocking the activity of T-bet

Reciprocal inhibition of Th1 and Th2 cells.

The antigenic stimulus that sends pre-Th cells down one path or the other also sets the stage for reinforcing the response.

A Th1 response inhibits the Th2 path in two ways:

• IFN-γ (shown above in red) and IL-12 inhibit the formation of Th2 cells
• IFN-γ also inhibits class-switching in B cells

A Th2 response inhibits the Th1 path:

• IL-4 suppresses Th1 formation (shown above in red)
• significance for public health: infection by helminths — common in the tropics — increases one's risk of viral and bacterial diseases, and in laboratory mice has been shown to enhance viral infections

Negative feedback of Th1 and Th2 cell formation

There is also evidence that late in the immune response, negative feedback mechanisms come into play to dampen the response.

• IL-4 kills (by apoptosis) the precursors of the dendritic cells that induce the Th2 path and thus further production of IL-4.
• IFN-γ may eventually turn off the Th1 response that produced it.

Th1 and Th2 cells have different chemokine receptors.

Chemokines are cytokines that are chemotactic for (attract) leukocytes. The members of one group, who share a pair of adjacent cysteine (C) residues near their N-terminal, are designated CC chemokines. Chemokines bind to receptors on the responding leukocyte. The receptors are transmembrane proteins with the chemokine binding site exposed at the surface of the plasma membrane. CC chemokine receptors are designated CCR.

With their different functions, we might expect that Th1 cells and Th2 cells would respond differently to chemokines. And so they do.

Th1 cells express the chemokine receptor CCR5 (but not CCR3).

Th2 cells express the chemokine receptor CCR3 (but not CCR5).

CCR3

One chemokine that binds to CCR3 is called eotaxin. It is secreted by epithelial cells and phagocytic cells in regions where allergic reactions are occurring.

CCR3 is found on all cells implicated in allergic responses (e.g., asthma). They are:

• Th2 cells
• eosinophils
• basophils

CCR5

CCR5 is found on

• Th1 cells, especially those in the lymphoid tissue of the intestine
• macrophages

CCR5 also acts — along with the CD4 molecule — as a coreceptor for HIV-1, the retrovirus that causes AIDS. This fact may explain

• why destruction of the lymphoid tissue of the intestine occurs soon after HIV infection;
• why certain HIV-infected men
  • with inherited mutations preventing the expression of CCR5 or
  • who produce high levels of the natural ligand for CCR5 (a chemokine designated CCL3L1, which presumably competes with HIV for access to CCR5)
  can tolerate their infection for long periods without progressing to a full-blown case of AIDS;
• the collapse of cell-mediated immunity in the late stages of AIDS

Example

One striking illustration: an AIDS patient with leukemia was given a bone marrow transplant from a donor whose cells expressed a nonfunctional version of CCR5. Two years later, the patient was not only cured of his leukemia but of AIDS as well.

Another: Gene therapy in which samples of a patient's CD4⁺ T cells were treated in vitro so that their CCR5 gene became nonfunctiona. Expanded in culture and then returned to the donor, five (of six) patients had their CD4⁺ T cell counts rebound.

Tfh Cells

Figure 15.4.8.2 Lymph node

Follicular helper T cells (Tfh) are CD4⁺ helper T cells found in nests of B cells called follicles — in the lymph nodes. When exposed (in the paracortical area of the lymph node) to cells presenting antigen to them, e.g., dendritic cells and a cocktail of cytokines they migrate into the follicles. The combined stimuli of antigen binding to their TCR and exposure to cytokines activate a transcription factor called Bcl-6 (first identified in a B-cell lymphoma). Bcl-6 turns on a collection of genes which, among other things, cause the Tfh cells to form an immunological synapse with those B cells expressing the antigen fragments in class II histocompatibility molecules that match their TCR.

Several other pairs of ligands and their receptors stabilize the synapse, including the interaction between CD28 on the Tfh cell and its ligand, B7, on the B cell. These binding interactions stimulate the B cell to

• undergo class switching with the synthesis of other antibody classes (except IgE)
• undergo affinity maturation
• form antibody-secreting plasma cells and memory B cells

This intense activity within the follicle forms a germinal center. It is not yet certain whether Tfh cells represent a distinct class of Th cells or are simply a further stage in the maturation of Th1, or Th2, or Th17 cells.

Th17 Cells

Th17 cells are a recently-identified subset of CD4⁺ T helper cells. They are found at the interfaces between the external environment and the internal environment, e.g., skin and lining of the GI tract. They probably start out like other "naive" Th cells, but when exposed to

• cells presenting antigen to them, e.g., dendritic cells
• several cytokines notably transforming growth factor-beta TGF-β and IL-6

they enter a pathway distinct from that of Th1, Th2, and Tfh cells. The combined stimuli of antigen binding to the TCR and exposure to the cytokinesactivate a nuclear retinoid receptor designated RORγt. This is a transcription factor that turns on a collection of genes which, among other things, leads to

• the synthesis and secretion of IL-17 (giving the cells their name)
• increased synthesis of the plasma membrane receptor for the interleukin IL-23. Interaction of IL-23 (perhaps secreted from nearby dendritic cells) with the receptor drives the rapid proliferation of the Th17 cells

Situated in the skin and the lining of the GI tract, Th17 cells are positioned to attack fungi and bacteria at those locations. They do this by secreting defensins and recruiting scavenging cells, especially neutrophils, to the site. The result: clearing away of the invaders with accompanying inflammation.

But inflammation is a double-edged sword. So it is not surprising that Th17 cells have been implicated as potent effectors of such damaging inflammatory disorders as

• Crohn's disease (an inflammation of the small intestine)
• Ulcerative colitis (inflammation of the large intestine)
• Psoriasis (inflammation of the skin)
• An animal model (in mice) of multiple sclerosis
• Rheumatoid arthritis

Summary Table

Type	Cytokine Stimulus	Master Transcription Factor	Effector Cytokine(s)	Main Target Cells	Effector Targets/Functions	Pathological Effects
Th1		T-bet	IFN-γ & TNF-β	Macrophages, dendritic cells	Intracellular pathogens	Autoimmunity; cell-mediated allergies
Th2	IL-4	GATA3		Eosinophils, basophils, B cells	Various helminths	Asthma and IgE-mediated allergies
Tfh		Bcl-6		B cells	Class Switch Recombination and Affinity Maturation of antibodies	Autoimmune diseases?
Th17	TGF-β plus IL-6 Inhibited by retinoic acid	RORγt		Neutrophils	Extracellular bacteria and fungi mediates inflammation	Autoimmune diseases
pTreg	TGF-β minus IL-6 Stimulated by retinoic acid and IL-2	Foxp3		all the other types of T cells	Immunosuppression; anti-inflammatory	None?

Contributors and Attributions

• John W. Kimball. This content is distributed under a Creative Commons Attribution 3.0 Unported (CC BY 3.0) license and made possible by funding from The Saylor Foundation.