Helper T Cells

• 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, namely B cells and cytotoxic T lymphocytes (CTLs). The help consists of secreted cytokines that stimulate the helped cells.

Types of Helper T Cells

• Th1
  • These participate in cell-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, in so doing, are essential for antibody-mediated immunity. Antibodies are needed to control extracellular pathogens (which — unlike intracellular parasites — are exposed to antibodies in blood and other body fluids).
• Th17
  • These protect surfaces (e.g., skin, lining of the intestine) against extracellular bacteria.

Origin of Helper T Cells

• 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 that determines which path they enter: the path leading to Th1 cells or the path leading to Th2 cells.

The antigen-presenting cells (APCs) are called dendritic cells (DCs). There are several subsets of them: some produced by monocytes and others derived from a progenitor cell that gives rise to both them and monocytes.

• ingest antigen by phagocytosis or pinocytosis;
• degrade it in lysosomes, and
• display fragments of the antigen at their surface for presentation to T cells.

  Discussion of how antigens are presented to T cells

• secrete cytokines.

(Dendritic cells can also present intact antigen directly to B cells. In this case, the engulfed antigen is not degraded in lysosomes but is returned to the cell surface for presentation to B cells bearing BCRs of the appropriate specificity.)

There are several kinds of dendritic cells that present antigens to T cells [Link].

Th1 Cells

• presents antigen to the T cell's receptor for antigen (TCR), and
• secretes interleukin 12 (IL-12) as well as interleukin 18 (IL-18) and IFN-γ (not shown).

The paracrine stimulation by these cytokines causes the Th1 cells to secrete their own lymphokines:

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

• stimulate macrophages to kill the bacteria they have engulfed;
• recruit other leukocytes to the site producing inflammation.

Th2 Cells

Th2 cells are produced when dendritic cells present antigen to the T cell's receptor for antigen (TCR) and, presumably, one or more paracrine stimulants other than IL-12. The identity of the cytokine(s) is still uncertain (indicated by a ? in the figure).

• 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.

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.

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

• IL-4 suppresses Th1 formation (shown above in red).

Negative feedback of Th1 and Th2 cell formation

• 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.

• Th2 cells
• eosinophils
• basophils

CCR5

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

• 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). CCL3L1 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.

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.

• cells presenting antigen to them, e.g., dendritic cells
• the cytokines
  • transforming growth factor-beta TGF-β and
  • IL-21 (in humans and mice) or IL-6 (in mice only)

• antigen binding to the TCR and
• exposure to TGF-β and IL-21

• the synthesis and secretion of IL-17 (giving the cells their name);
• the synthesis of a 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 bacteria on those surfaces. 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.

• 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.

Summary Table