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Friday, November 6, 2020



There are three main types of Bcell that respond to infection by secreting antibodies that target specific classes of microbes, with the particular function of each Bcell subset generally determined by their location. Follicular Bcells (also called B2 cells) express highly specific monoreactive Bcell receptors (BCRs), are present in the lymphoid follicles of the spleen and lymph nodes, and typically require Tcells in order to generate highaffinity antibodies, and to undergo class switching (Figure 7.21). However, as we shall discuss below, certain types of antigens (called Tindependent antigens) can promote Bcell activation without the help of Tcells. The antibodies thus formed are typically of low affinity and do not undergo class switching or somatic hypermutation but provide rapid protection from certain microorganisms and buy time for Tdependent Bcell responses to be made. Such rapid antibody responses are mediated by the “innate like” Bcells; B1 and marginal zone (MZ) Bcells, which express polyreactive BCRs that are of broad specificity and enable them to recognize multiple different kinds of evolutionarily conserved microbial antigens. In this way, they are similar to the Tolllike receptors (TLRs) expressed on conventional innate immune cells. Indeed, innatelike Bcells also express TLRs and can be directly acti­vated by PAMPs, act as APCs, and secrete cytokines, which places them at the interface between the innate and adaptive immune systems. Importantly, this innatelike Bcell response is positioned at strategic areas that are sensitive to microbial invasion, such as the skin, mucosa, and the marginal zone of the spleen, where the lymphatic and circulatory systems converge.


Figure 7.21 Interaction between Bcells and Tcells. Scanning electron microscope analysis of a cognate Bcell/Tcell pair, embedded in 3D collagen matrix.

1. Type 1 thymusindependent antigens

Certain antigens, such as bacterial lipopolysaccharides, when present at a sufficiently high concentration have the ability to activate a substantial proportion of the Bcell pool polyclonally (i.e., without reference to the antigen specificity of the surface receptor hypervariable regions). They do this through binding to surface molecules, such as TLRs as discussed in Chapter 1, which bypasses the early part of the biochemical pathway mediated by the specific antigen receptor. At concentrations that are too low to cause polyclonal activation through unaided binding to these mitogenic bypass molecules, the Bcell population with Ig receptors specific for these antigens will selectively and passively focus them on their surface, where the resulting high local concentration will suffice to drive the activation process (Figure 7.22a).


B‐cell recognition of (a) type 1 and (b) type 2 thymusindependent antigens

Figure 7.22 Bcell recognition of (a) type 1 and (b) type 2 thymusindependent antigens. The complex gives a sustained signal to the Bcell because of the long halflife of this type of molecule.

2. Type 2 thymusindependent antigens

Certain linear antigens that are not readily degraded in the body and that have an appropriately spaced, highly repeating determinant–Pneumococcus polysaccharide, Ficoll, damino acid polymers, and polyvinylpyrrolidone, for example – are also thymusindependent in their ability to stimulate Bcells directly without the need for Tcell involvement. Such antigens persist for long periods on the surface of follicular DCs located at the subcapsular sinus of the lymph nodes and the splenic marginal zone, and can bind to antigenspecific Bcells with great avidity through their multivalent attachment to the complementary Ig receptors that they crosslink (Figure 7.22b).

In general, the thymusindependent antigens give rise to predominantly lowaffinity IgM responses, some IgG3 in the mouse, and relatively poor, if any, memory. Neonatal Bcells do not respond well to type 2 antigens and this has important consequences for the efficacy of carbohydrate vaccines in young children.

This innate, Tcellindependent detection of microbial antigen is mediated by two types of Bcell: marginal zone (MZ) Bcells and B1 Bcells. MZ Bcells are located in the marginal zone of the spleen. This specialized area, located at the interface between the circulatory and lymphatic system, acts as a type of filter for bloodborne pathogens and MZ Bcells there constantly monitor the circulating levels of PAMP. In contrast, B1 Bcells are found in the skin and mucosal surfaces, areas continually under siege from pathogens, and act as a rapid first line of defense against microbial invasion. Importantly, activation of both of these innate Bcell types by simultaneous trigger of BCR and TLRs not only promotes a strong IgM and IgG3 response, but also presents antigen to Tcells, thus quickly activating the adaptive immune response. Mice specifically deficient in Bcell Myd88, an essential signal transducer for TLRs, show strong defects in their ability to mount an antibodymediated response to many types of infection, suggesting an important role for intrinsic TLR signaling in Bcell function.


T‐helper cells cooperate through protein carrier determinants to help B‐cells respond to hapten or equivalent determinants on antigens (Ag) by providing accessory signals. (For simplicity we are ignoring the MHC component and epitope processing in T‐cell recognition, but we won’t forget it.)

Figure 7.23 Thelper cells cooperate through protein carrier determinants to help Bcells respond to hapten or equivalent determinants on antigens (Ag) by providing accessory signals. (For simplicity we are ignoring the MHC component and epitope processing in Tcell recognition, but we won’t forget it.)

3. Thymusdependent antigens

The need for collaboration with Thelper cells

Many antigens are thymusdependent in that they provoke little or no antibody response in animals that have been thymectomized at birth and therefore have few Tcells (Milestone 7.1). Such antigens cannot fulfill the molecular requirements for direct stimulation: they may be univalent with respect to the specificity of each determinant; they may be readily degraded by phagocytic cells; and they may lack mitogenicity. If they bind to Bcell receptors, they will sit on the surface just like a hapten and do nothing to trigger the Bcell (Figure 7.23). Cast your mind back to the definition of a hapten – a small molecule such as dinitrophenyl (DNP) that binds to preformed antibody (e.g., the surface receptor of a specific Bcell) but fails to stimulate antibody production (i.e., stimulate the Bcell). Remember also that haptens become immunogenic when coupled to an appropriate carrier protein. Building on the knowledge that both T and Bcells are necessary for antibody responses to thymusdependent antigens (Milestone 7.1), we now know that the carrier functions to stimulate Thelper cells that cooperate with Bcells to enable them to respond to the hapten by providing accessory signals (Figure 7.23). It should also be evident from Figure 7.23 that, while one determinant on a typical protein antigen is behaving as a hapten in binding to the Bcell, the other determinants subserve a carrier function in recruiting Thelper cells.

T‐ and B‐cell interaction in a B‐cell follicle

Figure 7.24 T and Bcell interaction in a Bcell follicle. Multiple Tcell (red) and Bcell (green) pairs form at the T zone border within a Bcell follicle (arrowheads).

B‐cell handling of a thymus‐dependent antigen and presentation to an activated T‐cell

Figure 7.25 Bcell handling of a thymusdependent antigen and presentation to an activated Tcell. Antigen captured by the

surface Ig receptor is internalized within an endosome, processed, and expressed on the surface of the Bcell with MHC class II (see Figure 5.16). Costimulatory signals through the CD40–CD40L (CD154) interaction are required for the activation of the resting Bcell by the Thelper cell. In addition to CD40Lbased costimulation, helper Tcells also provide additional stimulation to the Bcell in the form of cytokines such as IL4.

Figure 7.26 Demonstration that endocytosed Bcell surface Ig receptors enter cytoplasmic vesicles geared for antigen processing. Surface IgG was crosslinked with goat antihuman Ig and rabbit antigoat Ig conjugated to 15 nm gold beads (large, dark arrow). After 2 minutes, the cell sections were prepared and stained with antiHLADR invariant chain (2 nm gold; arrowheads) and an antibody to a cathepsin protease (5 nm gold; open arrows). Thus the internalized IgG is exposed to proteolysis in a vesicle containing class II molecules. The presence of invariant chain shows that the class II molecules derive from the endoplasmic reticulum and Golgi, not from the cell surface. Note the clever use of differently sized gold particles to distinguish the antibodies used for localizing the various intravesicular proteins, etc.

Antigen processing by Bcells

The need for physical linkage of hapten and carrier strongly suggests that Thelpers must recognize the carrier determinants on the responding Bcell in order to provide the relevant accessory stimulatory signals. However, as Tcells only recognize processed membranebound antigen in association with MHC molecules, the Thelpers cannot recognize native antigen bound simply to the Ig receptors of the Bcell as naively depicted in Figure 7.23. All is not lost, however, as primed Bcells can present antigen to Thelper cells (Figure 7.24) – in fact, they work at much lower antigen concentrations than conventional presenting cells because they can focus antigen through their surface receptors. Antigen bound to surface Ig is internalized in endosomes that then fuse with vesicles containing MHC class II molecules with their invariant chain. Processing of the protein antigen then occurs as described in Chapter 5 (see Figure 5.16) and the resulting antigenic peptide is recycled to the surface in association with the class II molecules, where it is available for recognition by specific Thelpers (Figure 7.25 and Figure 7.26). The need for the physical union of hapten and carrier is now revealed; the hapten leads the carrier to be processed into the cell, which is programmed to make antihapten antibody and, following stimulus by the Thelperrecognizing processed carrier, it will carry out its program and ultimately produce antibodies that react with the hapten (is there no end to the wiliness of nature?).

Figure M7.1.1 The antibody response to some antigens is thymus dependent and, to others, thymus independent. The response to tetanus toxoid in neonatally thymectomized animals could be restored by the injection of thymocytes

Figure M7.1.2 The antibody response to a thymusdependent antigen requires two different lymphocyte populations. Different populations of cells from a normal mouse histocompatible with the recipient (i.e., of the same H2 haplotype) were injected into recipients that had been Xirradiated to destroy their own lymphocyte responses. They were then primed with a thymusdependent antigen such as sheep red blood cells (i.e., an antigen that fails to give a response in neonatally thymectomized mice; Figure M7.1.1) and examined for the production of antibody after 2 weeks. The small amount of antibody (Ab) synthesized by animals receiving bone marrow alone is due to the presence of thymocyte precursors in the cell inoculum that differentiate in the intact thymus gland of the recipient.

Milestone 7.1 TB collaboration for antibody production

In the 1960s, as the mysteries of the thymus were slowly unraveled, our erstwhile colleagues pushing back the frontiers of knowledge discovered that neonatal thymectomy in the mouse abrogated not only the cellular rejection of skin grafts, but also the antibody response to some but not all antigens (Figure M7.1.1). Subsequent investigations showed that both thymocytes and bone marrow cells were needed for optimal  antibody responses to such thymusdependent antigens (Figure M7.1.2). By carrying out these  transfers with cells from animals bearing a recognizable chromosome marker (T6), it became evident that the antibodyforming cells were derived from the bone marrow inoculum, hence the nomenclature T” for thymusderived lymphocytes and “B” for antibody forming cell precursors originating in the bone marrow. This convenient nomenclature has stuck even though bone marrow contains embryonic Tcell precursors, as the immunocompetent T and Bcells differentiate in the thymus and bone marrow, respectively.

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