Most effector T cells express members of the TNF family as membrane-associated proteins on the cell surface. These include TNF-α, the lymphotoxins (LTs), Fas ligand (CD178), and CD40 ligand, the latter two always being cell-surface associated. TNF-α is made by T cells in soluble and membrane-associated forms and assembles into a homotrimer. Secreted LT-α is a homotrimer, but in its membrane-bound form, LT-α is linked to a third, transmembrane member of this family called LT-β to form heterotrimers, called simply LT-β (see Section 9-2). The receptors for TNF-α and LT-α, TNFR-I and TNFR-II, form homotrimers when bound to their ligands. The trimeric structure is characteristic of all members of the TNF family, and the ligand-induced trimerization of their receptors seems to be the critical event in initiating signaling.
Fas ligand and CD40 ligand bind respectively to the transmembrane proteins Fas (CD95) and CD40 on target cells. Fas contains a ‘death’ domain in its cytoplasmic tail, and binding of Fas by Fas ligand induces death by apoptosis in the Fas-bearing cell (see Fig. 11.22). Other TNFR-family members, including TNFR-I, are also associated with death domains and can also induce apoptosis. Thus, TNF-α and LT-α can induce apoptosis by binding to TNFR-I.
CD40 ligand is particularly important for CD4 T-cell effector function; its expression is induced on TH1, TH2, TH17, and TFH cells, and it delivers activating signals to B cells and innate immune cells through CD40. The cytoplasmic tail of CD40 lacks a death domain; instead, it is linked downstream to proteins called TRAFs (TNF-receptor-associated factors). CD40 is involved in the activation of B cells and macrophages; the ligation of CD40 on B cells promotes growth and isotype switching, whereas CD40 ligation on macrophages induces them to secrete higher amounts of pro-inflammatory cytokines (for example, TNF-α) and become receptive to much lower concentrations of IFN-γ. Deficiency in CD40 ligand expression is associated with immunodeficiency, as we will learn in Chapter 13.
Summary.
Interactions between effector T cells and their targets are initiated by transient antigen-nonspecific adhesion. T-cell effector functions are elicited only when peptide:MHC complexes on the surface of the target cell are recognized by the receptor on an effector T cell. This recognition event triggers the effector T cell to adhere more strongly to the antigen-bearing target cell and to release its effector molecules directly at the target cell, leading to the activation or death of the target. The immunological consequences of antigen recognition by an effector T cell are determined largely by the set of effector molecules that the T cell produces on binding a specific target cell. CD8 cytotoxic T cells store preformed cytotoxins in specialized cytotoxic granules whose release is tightly focused at the site of contact with the infected target cell, thus killing it without killing any uninfected cells nearby. Cytokines and members of the TNF family of membrane-associated effector proteins are synthesized de novo by most effector T cells. Membrane-associated effector molecules can deliver signals only to an interacting cell bearing the appropriate receptor, whereas soluble cytokines can act on cytokine receptors expressed locally on the target cell, or on other cells at a distance. The actions of cytokines and membrane-associated effector molecules through their specific receptors, together with the effects of the cytotoxins released by CD8 cells, account for most of the effector functions of T cells.
T-cell-mediated cytotoxicity.