Homing of primed lymphoid cells to mucosal effector sites

After antigen-induced activation, proliferation and partial differentiation in MALT, lymphoid memory and effector cells migrate rapidly via regional lymph nodes and the peripheral blood circulation to various secretory effector sites (Fig. 14.3). The presence of SIgA antibodies to bovine p-lactoglobulin in neonatal breast milk ('witch milk') from infants fed cow's milk formula (Roberton et al., 1986) documents such early postnatal homing of primed intestinal B-cells to mammary glands. However, very few B-cells with IgA-pro-ducing capacity are actually present in the blood of newborns (< 8 per million mononuclear cells), although this number is remarkably increased (~ 600 per million mononuclear cells) after 1 month, reflecting the progressive exogenous stimulation of GALT (Nahmias et al., 1991). An initial early elevation of Ig-pro-ducing cells can be seen in preterm infants, especially in those with intrauterine infections, although the IgM class not unexpectedly dominates in such cases (Stoll et al., 1993). Altogether, these observations support the notion that mucosal immune cells are competent even before birth, at least during the final trimester, but that APCs need to undergo an activation process initiated by exogenous 'danger signals' enabling them to provide sufficient co-stimulatory signals to naive T-helper (Th) cells (Medzhitov and Janeway, 1997). This is further supported by the finding that fetal lamina propria T-cells (mainly CD4+) can be activated by mitogens or bacterial super-antigens in vitro (MacDonald and Spencer, 1993).

In this context, it is also interesting to note that intraepithelial lymphocytes (IELs) are present in human intestinal epithelium as early as 11 weeks of gestation (Orlic and Lev, 1977). As in adults, fetal IELs occur mainly in the villi of the small intestine and are dominated by CD3+ CD8+ T-cells (Brandtzaeg et al., 1998). Their numbers increase throughout the gestational period (Spencer et al., 1986b), which suggests that the migration of IELs into the epithelium is, to some extent, antigen-independent. However, stimulation by luminal factors clearly determines the numbers of IELs, as shown by their rapid post-natal increase, up to tenfold by the age of 1-2 years (Cerf-Bensussan and GuyGrand, 1991; Machado et al., 1994); this probably reflects the development of GALT, from which the intestinal IEL precursors may largely be derived (GuyGrand et al., 1978; Dunkley and Husband, 1987; Cuff et al., 1993). In a similar manner, germ-free animals have few IELs. Moreover, conventionalization of germ-free mice and rats has demonstrated a marked stimulatory effect of the commensal intestinal microflora and also its apparent impact on the T-cell receptor (TCR) repertoire of IELs (Helgeland and Brandtzaeg, 2000).

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