Antigen binding to BCRs or TCRs clusters these receptors and their associated invariant chains (and CD4 or CD8 co-receptors in the case of TCRs). This clustering activates a Src family cytoplasmic tyrosine kinase to phosphorylate tyro-sines on the cytoplasmic tails of some of the invariant chains. The phosphotyrosines then serve as docking sites for a second cytoplasmic tyrosine kinase, which becomes phosphorylated and activated by the first kinase; the second kinase then relays the signal downstream by phosphorylating other intracellular signaling proteins on tyrosines. Some of these early events in the signaling pathway activated by BCRs are shown in Figure 24–46.
Signaling through BCRs or TCRs and their associated proteins alone is not sufficient to activate a lymphocyte to proliferate and differentiate. Extracellular co-stimulatory signals produced by another cell are also required, and they are provided by membrane-bound proteins (see Figure 24–34) and secreted cytokines. Indeed, signaling through the BCR or TCR with insufficient co-stimulation can either eliminate the lymphocyte (clonal deletion) or inactivate it, with both of these mechanisms contributing to self-tolerance (see Figure 24–21). For a naïve T cell, an activated dendritic cell provides the co-stimulatory signals; these include the transmembrane B7 proteins, which are recognized by the co-receptor protein CD28 on the surface of the T cell (Figure 24–47A). For a B cell, an effector TH cell provides the co-stimulatory signals; these include the transmembrane CD40 ligand, which binds to CD40 receptors on the B cell (Figure 24–47B). The CD40 ligand on effector TH cells acts in two other situations: (1) it acts back on CD40 receptors on the dendritic cell surface to increase and sustain the activation of the dendritic cell, creating a positive feedback loop; and (2) it acts as a co-stimulatory signal on the surface of an effector TH1 cell, allowing the T cell to help activate an infected macrophage to destroy the pathogens it harbors.
In addition to receptors for co-stimulatory proteins, both B and T cells have inhibitory proteins on their surface that help regulate the cell’s activity, preventing excessive or inappropriate responses. Two such proteins expressed by T cells have attracted great attention because of their roles in suppressing the ability of T cells to inhibit cancer progression: CTLA4 and PD1 proteins inhibit T cell activity in different ways, and monoclonal antibodies against either or especially both can relieve the inhibition and allow T cells to dramatically destroy the tumors in some patients with metastatic cancer (see Figure 20–45).
Figure 24–45 The invariant chains associated with bCRs and TCRs.
(A) each Bcr is associated with two invariant heterodimers, each composed of an Igα and an Igβ polypeptide chain linked by a sulfide bond (red). (B) each Tcr is associated with an invariant cD3 complex composed of two disulfide-bonded ζ chains, two ε chains, and one δ and one γ chain; these chains form homodimers or heterodimers, as shown.