Naive T cells fall into two large classes, of which one carries the co-receptor CD8 on its surface and the other bears the co-receptor CD4. CD8 T cells all differentiate into CD8 cytotoxic T cells (sometimes called cytotoxic lymphocytes, or CTLs), which kill their target cells (Fig. 9.28). They are important in the defense against intracellular pathogens, especially viruses. Virus-infected cells display fragments of viral proteins as peptide:MHC class I complexes on their surface, and these are recognized by cytotoxic T lymphocytes.
Perhaps because the effector actions of these cells are so destructive, naive CD8 T cells require more co-stimulatory activity to drive them to become activated effector cells than do naive CD4 T cells. This requirement can be met in two ways. The simplest is priming by activated dendritic cells, which have high intrinsic co-stimulatory activity. In some viral infections, dendritic cells become sufficiently activated to directly induce CD8 T cells to produce the IL-2 required for their differentiation into cytotoxic effector cells, without help from CD4 T cells. This property of dendritic cells has been exploited to generate cytotoxic T-cell responses against tumors, as we will see in Chapter 16.
In the majority of viral infections, however, CD8 T-cell activation requires additional help, which is provided by CD4 effector T cells. CD4 T cells that recognize related antigens presented by the antigen-presenting cell can amplify the activation of naive CD8 T cells by further activating the antigen-presenting cell (Fig. 9.29). B7 expressed by the dendritic cell first activates the CD4 T cells to express IL-2 and CD40 ligand (see Sections 9-16 and 9-17). CD40 ligand binds CD40 on the dendritic cell, delivering an additional signal that increases the expression of B7 and 4-1BBL by the dendritic cell, which in turn provides additional co-stimulation to the naive CD8 T cell. The IL-2 produced by activated CD4 T cells also acts to promote effector CD8 T-cell differentiation.
9-20 CD4 T cells differentiate into several subsets of functionally different effector cells.
In contrast with CD8 T cells, CD4 T cells differentiate into several subsets of effector T cells that orchestrate different immune functions. The main functional subsets are TH1 (T helper 1), TH2, TH17, T follicular helper (TFH), and regulatory T (Treg) cells. The TH1, TH2, and TH17 subsets are elicited by different classes of pathogens and are defined on the basis of the different combinations of cytokines that they secrete (Fig. 9.30). These subsets cooperate with different innate cells of the myelomonocytic series and with innate lymphoid cells (ILCs) to form integrated ‘immune modules’ specialized for the clearance of the different classes of pathogens (see Fig. 3.37). One or the other of these subsets will typically become predominant as an immune response progresses, especially in persistent infections, autoimmunity, or allergies. As
Fig. 9.29 Most CD8 T-cell responses require CD4 T cells. Cd8 T cells recognizing antigen on weakly co-stimulatory cells may become activated only in the presence of Cd4 T cells interacting with the same antigen-presenting cell (apC). This happens mainly by an effector Cd4 T cell recognizing antigen on the antigen-presenting cell and being triggered to induce increased levels of co-stimulatory activity on the antigen-presenting cell. The Cd4 T cells also produce abundant IL-2 and thus help drive Cd8 T-cell proliferation. This may in turn activate the Cd8 T cell to make its own IL-2.