Primary Lymphoid Organs And Lymphopoiesis
The first strong evidence for distinct lymphocyte populations was the complementary effects in birds of early removal of the thymus (which mainly affects cell-mediated immunity) and the bursa of Fabricius (which affects antibody responses). A continuing puzzle has been the identification of what represents the bursa in mammals; despite a phase when ‘gut-associated lymphoid tissue’ was a popular candidate, current opinion considers there to be no true analogue, the liver taking over the function of B-cell maturation in the fetus, the bone marrow in the adult. The production of both B and T lymphocytes is a highly random and, at first glance, wasteful process, quite unlike any other form of haemopoiesis. It involves the rearrangement of genes to give each cell a unique receptor molecule (for details see Figs 12 and 13) and the elimination of all those cells that fail to achieve this, plus those that carry receptors that would recognize ‘self’ molecules and thus be potentially self-destructive (see Fig. 38). As recognition by T cells is more complex, involving the MHC as well as foreign antigen (see Figs 11, 12 and 18), production of T cells is a correspondingly more elaborate process, requiring two separate selection steps, one for self-MHC and one against self-antigens.
Both B- and T-cell development involves rapid and extensive cell proliferation. Cytokines (especially IL-2 and IL-7) have a key role in driving this cell expansion, and genetic defects in their receptors (e.g. common γ-chain deficiency) results in profound immunodeficiency (see Fig. 33). The repair of these genetic defects has been one of the first successful applications of the novel field of gene therapy to medicine.
The source of the earliest haemopoietic tissue, including the lymphocyte precursors.
In birds, B lymphocytes differentiate in the bursa of Fabricius, a cloacal outgrowth with many crypts and follicles, which reaches its maximum size a few weeks after birth and thereafter atrophies. Despite claims for the appendix, tonsil, etc., there is probably no mammalian analogue.
M Medulla; the region where the first stem cells colonize the bursal follicles.
C Cortex; the site of proliferation of the B lymphocytes.
During fetal life in mammals, the major haemopoietic and lymphopoietic organ.
SC Haematopoietic stem cells and stem cells of the B-cell lineage.
ST Stromal cells provide the structure and microenvironment in the bone marrow that allow B-cell differentiation.
HP Haemopoietic area. The anatomical location of lymphopoiesis in liver and bone marrow is not exactly known, but it presumably proceeds alongside the other haemopoietic pathways, in close association with macrophages and stromal cells. At least 70% of B cells die before release, probably because of faulty rearrangement of their immunoglobulin genes (see Fig. 13) or excessive self-reactivity.
S Sinus, collecting differentiated cells for discharge into the blood via the central longitudinal vein (CLV).
A two-lobed organ lying in the upper chest (in birds, in the neck), derived from outgrowths of the third and fourth branchial cleft and pharyngeal pouch. Like the bursa, it is largest in early life, although its subsequent atrophy is slower. In it, bone marrow-derived stem cells are converted into mature T lymphocytes. Remarkably, a second, much smaller thymus has only recently been discovered in the neck of mice. Some of the interpretations of classic thymectomy experiments on immune function may therefore have to be reinterpreted.
Thymocytes Immature T cells found within the thymus. The majority of thymocytes express both CD4 and CD8 on their surface, and are known as ‘double positives’. Over 90% of thymocytes die within the thymus before reaching maturity.
EP Epithelial cells within the thymus support thymic development by the production of cytokines and hormones, and by cell-surface interaction with thymocytes. Thymic epithelial cells express both class I and class II MHC molecules and have an important role in selection.
Thymic epithelial cells also have a special mechanism for expressing small amounts of a large number of ‘non-thymus’ proteins, which contributes to the establishment of self-tolerance (see Fig. 22). Failure of this mechanism in rare genetic diseases leads to generalized autoimmunity and death.
Hormones Numerous soluble factors extracted from the thymus (e.g. thymosins) were shown to stimulate the maturation of T cells, as judged by function or surface markers or both. Although several of these hormones are being tested for their ability to boost immunological function in a whole variety of diseases, their name is probably a misnomer as they are found in many other tissues and are not thought to have an important role in thymic development. The major maturing and differentiating factors are the cytokines (see Fig. 24), deficiencies of which can cause profound defects in lymphocyte development.
Cortex Dark-staining outer part packed with lymphocytes, compartmentalized by elongated epithelial cells. The process of proliferation and selection occurs mainly here.
Medulla Inner, predominantly epithelial part, to which cortical lymphocytes migrate before export via venules and lymphatics. The final stages of selection may occur at the cortico-medullary junction.
PCV Post-capillary venule, through which lymphocytes enter the thymic veins and ultimately the blood.
HC Hassall’s corpuscle; a structure peculiar to the thymus, in which epithelial cells become concentrically compressed and keratinized, possibly the site of removal of apoptotic cells. Although the function of Hassall’s corpuscle remains unclear, it may have a role in the pro- duction of TREG cells, regulatory cells that help to maintain tolerance to self (see Figs 15 and 22).
Selection Because of its importance and complexity, the process of selecting T lymphocytes for export has attracted intense study, and is currently considered to consist of the following stages.
1 CD4−CD8− (double-negative) cells proliferate in the outer region of the cortex, during which they become CD4+CD8+ (double positive) and rearrange their TCR genes.
2 Under the influence of thymic stromal cells, T lymphocytes whose TCR recognizes one of the available ‘self’ MHC molecules (see Figs 11 and 12) survive, and the rest die.
3 Cells that recognize an MHC class I molecule lose CD4 and retain CD8; those that recognize an MHC class II molecule lose CD8 and retain CD4; thus they are now ‘single positives’.
4 Under the influence of dendritic cells presenting ‘self’ antigens in the form of short peptides (for details see Fig. 18), potentially self- reactive T cells are eliminated.
5 The remainder, probably only about 2% of the starting population, are allowed to exit, and these make up the peripheral T-lymphocyte pool.