Protein antigens alone are unable to induce antibody responses in animals or humans who lack T cells, and they are therefore known as thymus-dependent or TD antigens, and typically involve antigen-specific T-cell help. The T cells involved are TFH cells that reside in the lymphoid tissues and are not fully differentiated TH1, TH2, or TH17 effector cells. To receive T-cell help, the B cell must display antigen on its surface in a form that a T cell can recognize. This occurs when antigen bound by surface immunoglobulin on the B cell is internalized and degraded within the B cell and peptides derived from it are returned to the cell surface in a complex with MHC class II molecules (see Fig. 10.2, first panel). When the TFH cell recognizes these peptide:MHC complexes, it provides the B cell with signals that favor survival and induce proliferation. These signals include the activation of CD40 on B cells by TFH expression of its ligand, CD40L (CD154), and production of various cytokines by TFH cells, including IL-21 (Fig. 10.3). CD40 signaling activates the non-canonical NFκB pathway (see Section 7-23) and enhances B-cell survival by inducing the expression of anti-apoptotic molecules such as Bcl-2. IL-21 signaling activates STAT3 and enhances cellular proliferation and differentiation into plasma cells and memory B cells. Other cytokines produced by TFH cells include IL-6, TGF-β, IFN-γ, and IL-4, which provide signals that can regulate the type of antibody produced, as we will see in Section 10-12. These cytokines are also made by other differentiated effector subsets (described in Chapter 9), but TFH cells are distinct from these. For example, TFH cells transcribe the IL-4 gene using regulatory elements that are independent of the transcription factors GATA-3 and STAT6, which are responsible for IL-4 production by TH2 cells.
While B-cell responses to protein antigens rely on help from T cells, some microbial constituents can induce antibody production in the absence of helper T cells. These microbial antigens are known as thymus-independent or TI antigens because they can induce antibody responses in individuals who have no T lymphocytes. Such antigens are typically highly repetitive molecules, such as the polysaccharides of bacterial cell walls, and can cross-link the BCR on B cells. In such cases, a second signal can be derived from direct recognition of a common microbial constituent such as LPS that can activate TLR signaling in the B cell (see Fig. 10.2, second panel), activating the NFκB pathway, as described in Chapter 3. Thymus-independent antibody responses provide some protection against extracellular bacteria, and we will return to them later.
Further differentiation can proceed to the germinal center, resting memory cells, or antibody-secreting plasma cells B-cell proliferation generates plasmablasts that form the primary focus TFH B cell AP-1 NFAT NF˜B Bcl-2 STAT3 germinal center B cell plasmacell memoryB cell various targets Antigen recognition by TFH cells induces signals that activate B cells IL-21 IL-6 TGF-°LFN-˛IL-4 STAT3 CD40 CD40L MHCII TCR