THE ACTIVATION OF T‐CELLS REQUIRES TWO SIGNALS
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 T‐cells on their own. Upon co‐stimulation via the CD28 receptor on the T‐cell, however, RNA and protein synthesis is induced, the cell enlarges to a blast‐like appearance, interleukin‐2 (IL‐2) 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 T‐cell (Figure 7.3).
Figure 7.3 Activation of resting T‐cells. Interaction of co‐stimulatory molecules leads to activation of resting T‐lymphocyte by antigen‐presenting cell (APC) on engagement of the T‐cell receptor (TCR) with its antigen–MHC complex. Engagement of the TCR signal 1 without accompanying co‐stimulatory signal 2 leads to anergy. Note, a cytotoxic rather than a helper T‐cell would, of course, involve coupling of CD8 to MHC class I. Signal 2 is delivered to a resting T‐cell primarily through engagement of CD28 on the T‐cell by B7.1 or B7.2 on the APC. ICAM‐1, intercellular adhesion molecule‐1; LFA‐1, lymphocyte function‐associated molecule‐1; VCAM‐1, vascular cell adhesion molecule‐1; VLA‐4, very late antigen‐4.
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 T‐cell is now exposed to a co‐stimulatory 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 T‐cell, although other molecules (such as IL‐1 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 (danger‐associated molecular patterns) are incapable of productively activating T‐cells. This is due to the relative absence of co‐stimulatory 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 IL‐1, GM‐CSF, and TNFα) that are produced by macrophages and neutrophils in the initial stages of infection are also capable of converting immature, poorly co‐stimulating DCs into mature DCs capable of providing the necessary signals. Activation of resting T‐cells can be blocked by anti‐B7, which renders the T‐cell 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 antigen‐specific cell provides a potential for targeted immunosuppressive therapy. However, unlike resting T‐lymphocytes, activated T‐cells proliferate in responseto a single signal.
Adhesion molecules such as ICAM‐1, VCAM‐1, and LFA‐3 are not intrinsically co‐stimulatory but greatly augment the effect of other signals by up to 100‐fold (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.