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Wednesday, October 21, 2020



Stimulation of the TCR by MHC–peptide (which can be mimicked by antibodies directed against the TCR or CD3 complex) is not sufficient to fully activate resting helper Tcells on their own. Upon costimulation via the CD28 receptor on the Tcell, however, RNA and protein synthesis is induced, the cell enlarges to a blastlike appearance, interleukin2 (IL2) synthesis begins and the cell moves from G0 into the G1 phase of the cell division cycle. Thus, two signals are required for the activation of a naive helper Tcell (Figure 7.3).

Figure 7.3 Activation of resting Tcells. Interaction of costimulatory molecules leads to activation of resting Tlymphocyte by antigenpresenting cell (APC) on engagement of the Tcell receptor (TCR) with its antigen–MHC complex. Engagement of the TCR signal 1 without accompanying costimulatory signal 2 leads to anergy. Note, a cytotoxic rather than a helper Tcell would, of course, involve coupling of CD8 to MHC class I. Signal 2 is delivered to a resting Tcell primarily through engagement of CD28 on the Tcell by B7.1 or B7.2 on the APC. ICAM1, intercellular adhesion molecule1; LFA1, lymphocyte functionassociated molecule1; VCAM1, vascular cell adhesion molecule1; VLA4, very late antigen4.

Antigen in association with MHC class II on the surface of a mature DC is clearly capable of fulfilling the requirement for both signals. Complex formation between the TCR and MHC–peptide provides signal 1, through the receptor–CD3 complex, and this is greatly enhanced by coupling of CD4 with the MHC. The Tcell is now exposed to a costimulatory signal (signal 2) from the mature DC. The most potent co stimulatory molecules are the B7 family ligands (CD80/ CD86) on the DC that interact with CD28 on the Tcell, although other molecules (such as IL1 and ligands for ICOS, CD2, and OX40) can also serve in this capacity.

Recall from Chapter 1 that immature DCs, that have not been exposed to PAMPs or DAMPs (dangerassociated molecular patterns) are incapable of productively activating Tcells. This is due to the relative absence of costimulatory molecules such as CD80/CD86 on the surface of immature DCs. However, a profound increase in the expression of these molecules occurs as a result of maturation of the DC subsequent to stimulation of its pattern recognition receptors with a PAMP or a DAMP. Inflammatory cytokines (such as IL1, GMCSF, and TNFα) that are produced by macrophages and neutrophils in the initial stages of infection are also capable of converting immature, poorly costimulating DCs into mature DCs capable of providing the necessary signals. Activation of resting Tcells can be blocked by antiB7, which renders the Tcell anergic (i.e., unresponsive to any further stimulation by antigen). As we shall see in later chapters, the principle that two signals activate but one may induce anergy in an antigenspecific cell provides a potential for targeted immunosuppressive therapy. However, unlike resting Tlymphocytes, activated Tcells proliferate in responseto a single signal.

Adhesion molecules such as ICAM1, VCAM1, and LFA3 are not intrinsically costimulatory but greatly augment the effect of other signals by up to 100fold (Figure 7.3); this is an important distinction. Early signaling events also involve the aggregation of lipid rafts composed of membrane subdomains enriched in cholesterol and glycosphingolipids. The cell mem­ brane molecules involved in activation become concentrated within these structures.

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