Immune System

Lymphocytes are central to all adaptive immune responses. They originate from stem cells in the bone marrow. Cells destined to become lymphocytes either mature in the bone marrow or exit the marrow and mature in the thymus (because they are sites of lymphocyte production, the bone marrow and thymus are termed the primary lymphoid organs). Lymphocytes that mature in the bone marrow make antibodies and are called B lymphocytes (B cells); whereas lymphocytes that mature in the thymus are called T lymphocytes (T cells). The T lymphocytes are further subdivided into functional subsets: cytotoxic T lymphocytes (Tc cells) generate cell-mediated immune responses and can destroy other cells that have pieces of antigen on their surface; helper T lymphocytes (Th cells) regulate the immune system, governing the quality and strength of all immune responses. Tc and Th cells are often termed CD8+ and CD4+ T cells, based on so-called "cluster designation" (CD) molecules found on their surface.

The notion that specificity in adaptive immune responses derives from a clonal distribution of antigen receptors, coupled with requisite receptor ligation for activation, is the central argument of the generally accepted clonal selection hypothesis. Simply put, while billions of different antigen receptors can be made (in terms of antigen-binding specificity), each lymphocyte makes only one kind. Engagement of this receptor is requisite for lymphocyte activation, so a given antigen activates only those lymphocytes whose receptors bind well, yielding appropriate specificity in the overall response.

Antigen recognition by lymphocytes. The B lymphocyte's antigen receptor is a membrane-bound version of the antibody it will secrete if activated. When activated, a B lymphocyte's secreted antibodies enter the blood and other body fluids, where the bind the antigen and help destroy it. In contrast, a T lymphocyte's antigen receptor (TcR) is not secreted, but instead binds antigen displayed on the surface of other cells. Further, while B lymphocytes can bind native antigens directly, T lymphocytes can only bind an antigen when it is degraded and presented. Antigen presentation occurs when degradation products of protein antigens become attached to molecules encoded by a group of genes called the Major Histocompatibility Complex (MHC) and displayed on cell surfaces. All vertebrates have a homologue of this gene complex; for example, the human MHC is named HLA. When proteins either are made within a cell or are ingested by phagocytosis, they may be degraded by a variety of systems. The resulting small peptides become associated with binding clefts in MHC molecules. This peptide-MHC molecule combination is then displayed on the cell's surface for recognition by T lymphocytes. Different categories of MHC molecules exist, encoded by different genes within the MHC. Class I MHC molecules tend to become associated with the degradation products of proteins that were synthesized inside the cell. Further, class I molecules generally present antigen to cytotoxic T cells, so if a cell makes class I MHC molecules, it can present antigen to cytotoxic T cells. Most kinds of cells in the body express MHC class I molecules, so nearly any cell that is synthesizing nonself proteins (such as those from a viral infection) can be destroyed by cytotoxic T cells. In contrast, class II MHC molecules present antigen to helper T cells, so a cell that makes class II MHC molecules can present antigen to helper T cells. Only a few kinds of cells, including dendritic cells, macrophages, and B lymphocytes, normally express class II MHC molecules and present antigen to Th cells.

Lymphocyte development, production, and receptor diversity. Since antigen receptor specificities are clonally distributed, the selectivity of immune responses relies on the constant availability of a large and diverse pre-immune lymphocyte pool. Towards this end, millions of lymphocytes are produced daily in the marrow and thymus. As lymphocytes develop and mature, they begin to express their surface-bound antigen receptor. The receptor's expression and specificity are established through a series of DNA rearrangement and splicing events that yield functional antigen receptor genes. Because the portion of the receptor molecule that will interact with antigen derives from such pseudorandom gene-splicing mechanisms, the number of permutations available to afford diversity among clonally distributed antigen-combining sites is enormous—in the range of 10¹².

Age-associated changes in lymphocyte development and selection. Lymphocyte production and selection changes with age. For example, the rate at which lymphocytes are generated in the thymus and bone marrow, which will dictate the turnover of mature lymphocytes in the periphery, has been shown to decrease with age. These shifts appear to reflect a combination of factors, which may include a lower frequency of successful antigen-receptor-gene expression, reflecting intrinsic changes in B cell progenitors. Further, failure or diminution of stromal trophic elements necessary for the survival of developing lymphocytes may occur with increasing age. Finally, shifts in the representation of various differentiation subsets, likely reflecting changes in the homeostatic processes that govern steady state numbers, shift with age.The mechanistic bases for these changes remain unclear, and are the subject of intense investigation.

In addition to changes in lymphocyte production, the degree of receptor diversity within both mature and developing lymphoid compartments may become truncated with age. This may alter the frequency or breadth of available primary clones that can engage in immune responses, affecting the outcome of immunization or vaccination. Similar to the factors contributing to reduced production rates, the basis for truncated antigen receptor diversity appears manifold. For example, it likely involves downstream effects precipitated by altered lymphocyte production and selection; but probably also originates from the life-long accumulation of expanded memory clones, which are the result of antigen-driven expansion, and perforce less diverse.