During B cell development in the bone marrow, before antigen stimulation, separate gene segments are brought together by site‑specific recombination that depends on a V(D)J recombinase. A VL gene segment recombines with a JL gene segment to produce a DNA sequence coding for the V region of a light chain, and a VH gene segment recombines with a D and a JH gene segment to produce a DNA sequence coding for the V region of a heavy chain. Each of the newly assembled V‑region coding sequences is then co‑transcribed with the appropriate C‑region sequence to produce an RNA molecule that codes for the complete Ig polypeptide chain.
By randomly combining inherited gene segments that code for the variable regions during B cell development, humans can make hundreds of different light chains and thousands of different heavy chains. Because the antigen‑binding site is formed where the hypervariable loops of the VL and VH domains come together in the final Ig molecule, the heavy and light chains can potentially pair to form Igs with millions of different antigen‑binding sites. A loss or gain of nucleotides at the site of gene‑segment joining increases this number enormously. The Igs made by such V(D)J recombination before antigen stimulation are IgMs and IgDs with low affinity for binding antigen, and they constitute the primary Ig repertoire.
Igs are further diversified following antigen stimulation in peripheral lymphoid organs by the AID‑ and helper‑T‑cell‑dependent processes of somatic hypermutation and class switch recombination, which together produce the high‑affinity IgG, IgE, and IgA Igs that constitute the secondary Ig repertoire. The process of class switching allows the same antigen‑binding site to be incorporated into antibodies that have different tails and therefore different biological properties.
Like antibody responses, T-cell-mediated immune responses are exquisitely antigen-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including most antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that have entered the interior of host cells, where they are invisible to B cells and antibodies. Much of the rest of this chapter is concerned with how T cells accomplish this feat.
T cell responses differ from B cell responses in at least two crucial ways. First, a T cell is activated by foreign antigen to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of an antigen‑presenting cell (APC), usually a dendritic cell in a peripheral lymphoid organ. One reason T cells require APCs for activation is that the form of antigen they recognize is different from that recognized by the Igs produced by B cells. Whereas Igs can recognize antigenic determinants on the surface of pathogens and soluble folded proteins, for example, T cells can only recognize fragments of protein antigens that have been produced by partial proteolysis inside a host cell. As mentioned earlier, newly formed MHC proteins capture these peptide fragments and carry them to the surface of the host cell, where T cells can recognize them.
The second difference is that, once activated, effector T cells act mainly at short range, either within a secondary lymphoid organ or after they have migrated to a site of infection. Effector B cells, by contrast, secrete antibodies that can act far away. Effector T cells interact directly with another host cell in the body, which they either kill (if it is an infected host cell, for example) or signal in some way (if it is a B cell or macrophage, for example). We will refer to such host cells as target cells. As is the case with APCs, target cells must display an antigen bound to an MHC protein on their surface for a T cell to recognize them.