T Cells

Various phenotypes have been reported for the earliest bone marrow-derived T cell precursors; however, strong evidence exists that some cells become committed to the T cell lineage prethymically (Rodewald et al. 2003; Rothenberg et al. 2003). Prothymocytes found in the fetal liver at 7 weeks postconception are positive for CD7, CD45, and cytoplasmic CD3. CD7+ T cell precursors seed the thymus at 8 to 9 weeks of gestation, increase their expression of T cell receptor (TCR) gd chain from 9.5 weeks to birth (Haynes et al. 1988; Haynes et al. 1989a; reviewed in: Holt and Jones 2000), and first express TCR ap chain at 10 weeks (Haynes et al. 1989a). Prethymic T cell precursors have also been documented to express Thy-1 and low levels of CD4 (Chaplin 2003). Another report states that the most primitive precursors of T cells in the thymus are CD34+, CD38lQ (reviewed in: Rothenberg et al. 2003), whereas a fourth lists the expression of the T cell markers CD3, CD4, CD5, and CD8 on fetal thy-mocytes at 10 weeks of gestation (Lobach and Haynes 1987). What is clear even without reference to phenotype is that the majority of pre-T cells requires the thymic microenvironment for maturation, moving from the cortex of the newly formed thymus to the medulla during maturation (reviewed in: Rothenberg et al. 2003).

Thymic T cell precursors proceed along ordered pathways of development. Gene rearrangement in developing thymocytes occurs at approximately week 11, resulting first in y5TCR expression, followed by ap TCR expression (reviewed in: West 2002). By 15 to 20 weeks of gestation, the number of T cell precursors in the thymus is relatively similar to those found postnatally (Wilson et al. 1992). Sequential expression of coreceptors CD3, CD4, and CD8 proceeds from TCR gene expression, and the expression of these molecules enables the thymocyte to respond to MHC molecules expressed on thymic epithelial and dendritic cells. The complex process of thymic education follows, culminating in an enormous reduction in the total lymphocyte population emerging from the thymus (Rothenberg et al. 2003).

CD2+ CD3+ CD5+ T cells detectable in the fetal circulation at about 15 to 16 weeks of gestation (Haynes et al. 1989b) coincide with maturation of the thymus medulla (von Gaudecker 1991) and with the beginning of an intense expansion of T cells occurring between weeks 14 and 26 of gestation (West 2002). Interestingly, immature T cells express CD45RO until the final step of maturation in the thymus, when T cells begin expressing the "naïve" marker CD45RA. Therefore, the increased frequency of CD45RO+/RA- T cells found in the spleen and blood of premature babies (Fujii et al. 1992; Hannet et al. 1992) may indicate very immature, rather than a previously activated, T cell population (Fujii et al. 1992; Holt and Jones 2000).

Functional maturation of T cells as tested by responsiveness to mitogens and alloantigens occurs at the end of the first trimester and the beginning of the second trimester (11 to 18 weeks of gestation) (Holladay and Smialowicz 2000; Holt and Jones 2000; West 2002). In particular, fetal thymus lymphocytes respond to PHA by 12 weeks and ConA by 13 to 14 weeks of gestation. Lymphocytes from spleen or peripheral blood respond to PHA and ConA by 16 weeks and 18 weeks of gestation, respectively. The ability of fetal lymphocytes to respond to and cause stimulation of allogeneic lymphocytes in a mixed-lymphocyte reaction (MLR) has been variably reported as occurring between weeks 11 to 19 of gestation (Holladay and Smialowicz 2000; West 2002). Overall, the T cell compartment of the human immune system has acquired a significant level of functional maturity in terms of responding to antigens by birth.

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