7/21/2019 Ch 7 Antibody 7E13

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CD45 molecules, also known as the leukocyte commonantigen, are excluded to an outer ring. The precisearrangement of the immunological synapse is cell specificand may be different on T cells and other cells such asNK cells.

Although the interaction between CD4+ T cells andAPCs has been reasonably well studied, that betweenCD8+T cells and APCs is less well understood. CD4+ cellshelp in the activation of most CD8+ T cells. Because asingle interdigitating DC (IDC) can bind many T cells, ithas been proposed that activation takes place in a clusterof CD4+ and CD8+ T cells gathered on the surfaceof IDCs.

T CELL ACTIVATION LEADS TOPRODUCTION OF IL-2 AND HIGH-AFFINITY IL-2RReceptors on the surface of T cells signal to the interior ofthe cell using signal transduction pathways that arecommon to many other cell types, including B cells. A key

principle is the clustering of receptors upon ligandbinding. This leads to activation of associated tyrosinekinases, which phosphorylate tyrosine residues in thecytoplasmic tails of the clustered receptors, followed byrecruitment of additional kinases and signaling molecules,in cascades. The end-result of these complex pathways isthe induction of gene synthesis by the activation oftranscription factors (Fig. 7.21).

Activation is initiated by the actions oftyrosine kinasesTCR and chains are associated with the CD3, , and molecules, the and chains (see Fig. 5.3), and theenzyme Lck (p56lck), which is attached to the intracellularportions of CD4 or CD8 (see Fig. 7.21). The label p56 lck

signifies a lymphocyte-specific tyrosine kinase of 56 kDa.Recognition of an antigenMHC molecule complex by

the TCR and ligation of co-stimulatory molecules initiatesthe signaling events.

The earliest events involve tyrosine kinases of the Srcfamily, particularly Lck associated with CD4 and CD8,and Fyn, which phosphorylate target sequences foundin the chain (also present on Ig, Ig, and FcR, seeFig. 3.20), termed immunoreceptor tyrosine-basedactivation motifs (ITAMs).

Phosphorylation of the ITAMs initiates a series of steps(see Fig. 7.21), that lead to the activation of transcriptionfactors and their translocation to the nucleus. Thetranscription factors act on genes required for T cell

activation, including the IL-2 and the IL-2 receptor(IL-2R) genes.

Q. What occurs when a cell generates both a cytokine and

the receptor for that cytokine?

A. This allows autocrine stimulation, where the cell can activate

itself as well as similar cells in the immediate vicinity.

Cell division occurs after IL-2 production and issecondary to ligation of the IL-2R.

T CELL ACTIVATION LEADS TO PRODUCTION OF IL-2 AND HIGH-AFFINITY IL-2R

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Diagram of an immunological synapse

Fig. 7.19 Sets of receptors and their ligands

TCRpeptideMHC molecule; CD2CD48; CD28CD80 all

contribute to the formation of a synapse. The TCR assembles

with MHC moleculeantigen peptide molecules and this

moves to form a cluster. LFA-1ICAM-1 interactions arerelegated to the perimeter of the raft.

APCICAM-1

(CD54)class I

CD2CD8

T cell

LFA-1

ICAM-1

(CD54)

LFA-1

TCR

CD48

CD28

B7-1/B7-2

(CD80/86)

Color-enhanced reconstruction of an immunological

synapse

Fig. 7.20 A live-cell fluorescence image, showing the

peripheral zone of adhesion molecules (red) surrounding the

core containing TCRs (green), is superimposed on a scanning

electron micrograph of a T cell (purple) interacting with a DC

(dark green). (Courtesy of Dr Mike Dustin and Science)