Info

Cell Type

Class II MHC

Costimulators

Principal Function

Dendritic cells

Constitutive; increases with maturation; increased by IFN-y

Constitutive; increases with maturation; inducible by IFN-y, CD40-CD40L interactions

Initiation of T cell responses to protein antigens (priming)

Macrophages

Low or negative; inducible by IFN-y

Inducible by LPS, IFN-y, CD40-CD40L interactions

Effector phase of cell-mediated immune responses (T cell-enhanced killing of phagocytosed microbes)

B lymphocytes

Constitutive; increased by IL-4

Induced by T cells (CD40-CD40L interactions), antigen receptor cross-linking

Antigen presentation to CD4+ helper T cells in humoral immune responses (cognate T cell-B cell interactions)

Vascular endothelial cells

Inducible by IFN-y ; constitutive in humans

Constitutive (inducible in mice)

May promote activation of antigen-specific T cells at site of antigen exposure

Various epithelial and mesenchymal cells

Inducible by IFN-y

Probably none

No known physiologic function

IFN-y, interferon-y ; IL-4, interleukin-4; LPS, lipopolysaccharide.

• APCs display peptide-MHC complexes for recognition by T cells and also provide additional stimuli to the T cells that are required for the full responses of the T cells. These stimuli, sometimes called "second signals," are more important for activation of naive T cells than for previously activated effector and memory cells. The membrane-bound molecules of APCs that serve to activate T cells are called costimulators because they function together with antigen in T cell stimulation. APCs also secrete cytokines that play critical roles in T cell differentiation into effector cells. These costimula-tors and cytokines are described in Chapter 9.

• The antigen-presenting function of APCs is enhanced by exposure to microbial products. This is one reason that the immune system responds better to microbes than to harmless, nonmicrobial substances. Dendritic cells and macrophages express Toll-like receptors and other microbial sensors (see Chapter 4) that respond to microbes by increasing the expression of MHC molecules and costimulators, by improving the efficiency of antigen presentation, and by activating the APCs to produce cytokines, all of which stimulate T cell responses. In addition, dendritic cells that are activated by microbes express chemokine receptors that stimulate their migration to sites where T cells are present. The induction of optimal T cell responses to purified protein antigens requires that the antigens be administered with substances called adjuvants. Adjuvants either are products of microbes, such as killed myco-bacteria (used experimentally), or they mimic microbes and enhance the expression of costimulators and cytokines as well as the antigen-presenting functions of APCs (see Chapter 9).

• APCs that present antigens to T cells also receive signals from these lymphocytes that enhance their antigen-presenting function. In particular, CD4+ T cells that are activated by antigen recognition and costimulation express surface molecules, notably one called CD40

ligand (CD154), that binds to CD40 on dendritic cells and macrophages, and the T cells secrete cytokines such as interferon-y (IFN-y) that bind to their receptors on these APCs. The combination of CD40 signals and cytokines activates the APCs, resulting in increased ability to process and present antigens, increased expression of costimulators, and secretion of cytokines that activate the T cells. This bidirectional interaction between APCs displaying the antigen and T lymphocytes that recognize the antigen functions as a positive feedback loop that plays an important role in maximizing the immune response (see Chapter 9).

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