Cellular events

Antigen presentation takes place very rapidly upon entry of antigen into lymphoid tissues. Presumably macrophages and Langerhans-dendritic cells take up the antigen and are responsible for the early recruitment and activation of CD4 T cells. B cells that have surface immunoglobulin molecules with specificity for the antigen also participate by binding the antigen, processing it and presenting it to the CD4 T cells.

Antigen presentation comprises other events besides processing of the antigen and formation of the peptide-MHC complex. First, the antigen-specific T cells must establish physical contact with the APCs. Second, T cells require to interact with two sets of molecules provided by APCs: costimulatory molecules, in order to enter cell cycle and to activate cytokine-specific genes; and cytokines that modulate their expression of different genes. Clearly T cell activation is a multistage process involving a 'signal 1', the engagement of the T cell receptor, and various 'signal 2'. The molecules that primarily promote physical contact are termed cell adhesion molecules (or CAMs), while those that primarily promote growth and differentiation are termed costimulators. Details of the APC-T cell interaction are given in the Antigen-Presenting Cell article which contains a table showing the molecules involved.

The interaction between the APCs and the CD4 T cells is physically manifested by close cell-to-cell contact. This intimate APC-CD4 T cell contact is favored by cell adhesion molecules the lymphocyte functional antigen-1 (LFA-1) on the T cells with its corresponding ligands, ICAM-1, ICAM-2 and ICAM-3 on the APCs; and the CD2 molecule with its counter-receptor. The functional effects of the interaction are reciprocal - macrophages will be stimulated to release cytokines, B cells will proliferate and differentiate, while the CD4 T cells will also proliferate and release cytokines.

Costimulator molecules are key in determining that the engagement of the T cell antigen receptor to the MHC-peptide complex is a productive interaction. These include the B7-1 and B7-2 molecules on APCs (and their coreceptors CD28 and CTLA-4 on T cells), and the CD40 molecule on B cells in particular, and the CD40 ligand coreceptors on T cells. These costimulator molecules may act by inducing early release by T cells of growth factors such as interleukin-2 (IL-2) and/or by regulating the expression of receptors for growth factors, and by inhibiting apoptosis. In vitro experiments indicate that exposure of T cells to fixed APCs (which cannot provide costimulatory molecules) results in an absent response. Such T cells, in fact, may develop an unresponsive or anergic state. Costimulatory molecules of APCs are expressed in low amounts. The representation of their expression is one component that initiates productive presentation. Finally to note is that several cytokines from APCs modulate the T cell response during antigen presentation. Included are IL-la and 3, tumor necrosis factor -a (TNFa), IL-6 and IL-12. This latter cytokine is key in the differentiation of T cells to the TH1 subset.

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