Comparison of B- and T-Cell Development

In closing this chapter, it is instructive to consider the many points of comparison in the development of the two arms of the adaptive immune system: B cells and T cells (Table 9-5). Both types of lymphocytes include two distinct cell lineages, of which one (γδ T cells and B-1 B cells) disperses to its own particular peripheral niches during fetal development, there to function as a self-renewing population until the death of the host. Beginning around the time of birth and continuing through adult life, the development of conventional B cells (B-2, follicular) and T cells (αβ) commences in the bone marrow, starting with hematopoietic stem cells. B and T cells share the early phases of their developmental programs, as they pass through progressively more differentiated stages as MPPs, ELPs, and CLPs. At the ELP and CLP stages, T-cell progenitors leave the bone marrow and migrate to the thymus to complete their development, leaving B-cell progenitors behind. In mammals, B cells do not have an organ analogous to the thymus in which to develop into mature, functioning cells, although birds do possess such an organ—the bursa of Fabricius.

TABLE 9-5 Comparison between T-cell and B-cell development

Structure or process	B cells	T cells
Lineage seeds the periphery during fetal development	+ (B-1a)	+ (γδ)
Develop from HSCs in the bone marrow	+ (B-2, MZ)	+ (αβ)
Development continues in the thymus	−	+
Ig heavy-chain or TCR β-chain gene rearrangement begins with D-J and continues with V-DJ recombination	+	+
The H chain (BCR) or β chain (TCR) is expressed with a surrogate form of the second chain on the cell surface. Signaling from this pre-BCR or pre-TCR is necessary for development to continue	+	+
Signaling through the pre-B-cell receptor or pre-TCR results in proliferation and initiation of the rearrangement of the second chain κ/λ (BCR) or α (TCR)	+	+
The κ/λ (BCR) or α/γ (TCR) chain bears only V and J segments	+	+
Signaling from the completed receptor is necessary for survival (positive selection)	+	+
Positive selection requires recognition of self components	+ (true for the minority B-1a and MZ subsets)	+ (low-affinity binding of self MHC and self peptide in the thymus is necessary for positive selection)
Receptor editing of κ/λ (BCR) or α/γ (TCR) chain	+ (to eliminate self-reactive BCR)	+ (rearrangements of remaining TCR α V and J segments may continue until a TCR is formed that can recognize self peptide/MHC to allow positive selection)
Immature cells bearing high-affinity autoreactive receptors are eliminated by apoptosis (negative selection)	+ (immature and T1 B cells)	+
Negative selection involves expression of peripheral tissue self antigens in the primary lymphoid organs	−	+ (peripheral tissue self antigens are expressed in the thymus under the influence of the AIRE transcription regulator)
Negative selection involves recognition of MHC-presented peptides	−	+
Antigen receptor allelic exclusion	+ (heavy and light chains)	+ (TCR β chain; many T cells display more than one TCR α chain if the first that was expressed does not generate a TCR recognizing self MHC)
>90% of lymphocytes are lost prior to export to the periphery	+	+
Processes in the periphery allow establishment of tolerance to antigens not expressed in the primary lymphoid organs	+	+

Note: Unless noted otherwise, the comparisons in this table refer to the predominant αβ T cell and follicular B-2 cell subsets.

Both B and T cells initiate V(D)J rearrangement for one of their chains, which are expressed with a surrogate second chain. The resulting pre-BCR or pre-TCR signals cells that the first chain rearranged productively, and to go ahead and rearrange the second receptor gene family.

B cells expressing mIgM BCR and T cells expressing αβ TCR both must pass through stages of positive selection, in which those cells capable of receiving survival signals are retained at the expense of those that cannot. For T cells positive selection occurs only if the TCR recognizes peptide bound to self MHC, needed to generate a TCR repertoire that will be useful in responding to foreign peptide–MHC complexes. The process of positive selection of B-2 cells, while not fully understood, may involve spontaneous tonic signaling, independent of any ligand binding. Conventional B and T cells must also survive the process of negative selection, in which lymphocytes with high affinity for self antigens are deleted, induced to undergo receptor editing (B-2 B cells only), or inactivated, before they become mature functional cells in the periphery. In contrast, B-1 and marginal zone B cells are positively selected by low-affinity recognition of self antigens.

With the expression of high levels of IgD on the cell surface and the necessary adhesion molecules to direct their recirculation, development of the mature, follicular B-2 cell is complete and, for a few weeks to months, it will recirculate, ready for antigen contact in the context of T-cell help and subsequent differentiation to antibody production. For the final, antigen-stimulated stages of B-cell differentiation, the reader is directed to Chapter 11.

As with many physiological systems in the body, the functions of the immune system gradually decline during aging. Changes in B-cell development and responses, including diminished production of certain natural antibodies that may be beneficial, are described in Clinical Focus Box 9-3.

CLINICAL FOCUS BOX 9-3

B-Cell Development and Function in the Aging Individual

People of retirement age and older represent a growing segment of the population, and these older individuals expect to remain active and productive members of society. However, physicians and immunologists have long known that the elderly are more susceptible to infection than are young men and women, that vaccinations are less effective in older individuals, and that the elderly suffer from conditions that increase with age, including atherosclerosis and dementia, both of which have immune/inflammatory components. In this feature, we explore the differences in B-cell development between younger and older vertebrates, which may account for some of these immunological disparities between adult and older individuals.

Aging individuals display deficiencies in many aspects of B-cell function, including poor antibody responses to vaccination, inefficient generation of memory B cells, and an increase in the expression of autoimmune disorders. Current research demonstrates that aging individuals display a range of shortcomings in developing B cells that affect their immune status.

Experiments employing reciprocal bone marrow chimeras—in which aging HSCs were transplanted into young recipients or HSCs from young mice were injected into aging recipients—have shown that suboptimal processes of B-cell development in aging individuals result from deficiencies in both the aging stem cells and in the supporting stromal cells. For example, bone marrow stromal cells from aging mice secrete lower levels of IL-7 than do stromal cells from younger animals. However, a study of isolated, aging B-cell progenitors reveals that they also respond less efficiently to IL-7 than do B cells from younger mice, and so the IL-7 response in aging individuals is affected at both the producing and recipient-cell levels.

Indeed, the problems encountered by developing B cells from aging individuals start at the very beginning of their developmental program. The epigenetic regulation of HSC genes in aging mice is compromised, resulting in diminished levels of HSC self-renewal. Furthermore, the balance between the production of myeloid versus lymphoid progenitors is shifted in older individuals, with down-regulation of genes associated with lymphoid specification and a correspondingly enhanced expression of genes specifying myeloid development. The net effect of these changes in the HSC population is a reduction in the numbers of early B-cell progenitors, which is reflected in a decrease in the numbers of pro- and pre-B-cell precursors at all stages of development.

Detailed studies of the expression of particular genes important in B-cell development demonstrate that the expression of important transcription factors, such as E2A, is reduced in older animals. Furthermore, the genes for the RAG and λ5 surrogate light-chain proteins are down-regulated in older animals, contributing to the reduction in bone marrow output of immature B cells.

Thus, multiple mechanisms help to explain why the numbers of B cells released from the bone marrow are smaller in aging than in younger individuals. But is the antigen recognition repertoire—the quality—as well as the quantity of B cells different between the two populations? The answer to this question has come from the development of techniques that enable a global assessment of repertoire diversity. Study of the sizes and sequences of CDR3s from large numbers of human B cells suggests that in aging individuals the size of the repertoire (the number of different B-cell receptors an individual expresses) is drastically diminished and that this decrease in repertoire diversity correlates with a reduction in the health of the aging patient. The mechanisms for this age-related repertoire truncation are the subject of ongoing studies.

Intriguing recent results also suggest that reductions in human B-1 cells and their natural antibody products may contribute to aging-associated conditions including atherosclerosis and neurodegenerative conditions such as Alzheimer’s. Healthy individuals produce natural IgM antibodies that react with oxidized low-density lipoproteins (oxLDL) that contribute to plaque formation in blood vessels. These IgM antibodies appear to be protective: the levels of these IgM antibodies in people in their 60s were found to be inversely correlated with development of cardiovascular problems. In the second example, neurodegeneration, healthy people often have natural antibodies that react with amyloid and tau proteins, which can form abnormal plaques and tangles, respectively, that have been implicated in contributing to Alzheimer’s. Such natural antibodies, which may help to clear the aggregated proteins and improve cell survival, appear to be diminished in individuals with Alzheimer’s. Passive transfer of such natural antibodies into animals has reduced the abnormal amyloid and tau proteins and improved brain pathology and behavior.

These and other findings suggest that reduction in natural antibodies may lead to increased susceptibility to certain age-related conditions; indeed, age-associated declines in the number of B-1 cells have been observed in mice and humans. These results also raise the exciting possibility that passive transfer of natural antibodies reactive with appropriate targets may help restore a natural mechanism by which our immune system might protect us from tissue damage.

REFERENCES

• Cancro, M. P., et al. 2009. B cells and aging: molecules and mechanisms. Trends in Immunology 30:313.
• Dorshkind, K., E. Montecino-Rodriguez, and R. A. Signer. 2009. The ageing immune system: is it ever too old to become young again? Nature Reviews Immunology 9:57.
• Labrie, J. E. III, et al. 2004. Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. Journal of Experimental Medicine 200:411.
• Van der Put, E., et al. 2003. Aged mice exhibit distinct B cell precursor phenotypes differing in activation, proliferation and apoptosis. Experimental Gerontology 38:1137.

Key Concepts:

• There are many similarities between B-cell and T-cell development, including the gradual commitment to the cell lineage and the sequential rearrangement of antigen receptor genes, with checkpoints that test for productive rearrangement and expression of receptor polypeptides and select for cells with appropriate specificities.
• The results of these developmental processes usually are mature B and T cells with appropriate antigen receptor repertoires that will protect us from infections and avoid undesirable autoreactivity.